transforming-growth-factor-beta and Vascular-Diseases

Skin is a key organ maintaining internal homeostasis by performing many functions such as water loss prevention, body temperature regulation and protection from noxious substance absorption, microorganism intrusion and physical trauma. Skin ageing has been well studied and it is well known that physiological changes in the elderly result in higher skin fragility favouring the onset of skin diseases. For example, prolonged and/or high-intensity pressure may suppress local blood flow more easily, disturbing cell metabolism and inducing pressure injury (PI) formation. Pressure injuries (PIs) represent a significant problem worldwide and their prevalence remains too high. A higher PI prevalence is correlated with an elderly population. Newborn skin evolution has been less studied, but some data also report a higher PI prevalence in this population compared to older children, and several authors also consider this skin as physiologically fragile. In this review, we compare the characteristics of newborn and elderly skin in order to determine common features that may explain their fragility, especially regarding PI risk. We show that, despite differences in appearance, they share many common features leading to higher fragility to shear and pressure forces, not only at the structural level but also at the cellular and molecular level and in terms of physiology. Both newborn and elderly skin have: (i) a thinner epidermis; (ii) a thinner dermis containing a less-resistant collagen network, a higher collagen III:collagen I ratio and less elastin; (iii) a flatter dermal-epidermal junction (DEJ) with lower anchoring systems; and (iv) a thinner hypodermis, resulting in lower mechanical resistance to skin damage when pressure or shear forces are applied. At the molecular level, reduced expression of transforming growth factor β (TGFβ) and its receptor TGFβ receptor II (TβRII) is involved in the decreased production and/or increased degradation of various dermal extracellular matrix (ECM) components. Epidermal fragility also involves a higher skin pH which decreases the activity of key enzymes inducing ceramide deficiency and reduced barrier protection. This seems to be correlated with higher PI prevalence in some situations. Some data also suggest that stratum corneum (SC) dryness, which may disturb cell metabolism, also increases the risk of PI formation. Besides this structural fragility, several skin functions are also less efficient. Low applied pressures induce s

Topics: Adolescent; Adult; Aged; Child; Collagen; Extracellular Matrix; Humans; Infant, Newborn; Pressure Ulcer; Skin Physiological Phenomena; Transforming Growth Factor beta; Vascular Diseases

In this review, we discuss the role of transforming growth factor-beta (TGF-β) in the development of pulmonary vascular disease (PVD), both pulmonary arteriovenous malformations (AVM) and pulmonary hypertension (PH), in hereditary hemorrhagic telangiectasia (HHT). HHT or Rendu-Osler-Weber disease is an autosomal dominant genetic disorder with an estimated prevalence of 1 in 5000 persons and characterized by epistaxis, telangiectasia and AVMs in more than 80% of cases, HHT is caused by a mutation in the ENG gene on chromosome 9 encoding for the protein endoglin or activin receptor-like kinase 1 (ACVRL1) gene on chromosome 12 encoding for the protein ALK-1, resulting in HHT type 1 or HHT type 2, respectively. A third disease-causing mutation has been found in the SMAD-4 gene, causing a combination of HHT and juvenile polyposis coli. All three genes play a role in the TGF-β signaling pathway that is essential in angiogenesis where it plays a pivotal role in neoangiogenesis, vessel maturation and stabilization. PH is characterized by elevated mean pulmonary arterial pressure caused by a variety of different underlying pathologies. HHT carries an additional increased risk of PH because of high cardiac output as a result of anemia and shunting through hepatic AVMs, or development of pulmonary arterial hypertension due to interference of the TGF-β pathway. HHT in combination with PH is associated with a worse prognosis due to right-sided cardiac failure. The treatment of PVD in HHT includes medical or interventional therapy.

Topics: Activin Receptors, Type II; Animals; Arteriovenous Malformations; Endoglin; Humans; Hypertension, Pulmonary; Lung Diseases; Mutation; Risk; Signal Transduction; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta; Vascular Diseases

Vascular calcification is a major risk factor for cardiovascular morbidity and mortality. A full understanding of the signalling pathways mediating vascular calcification is crucial not just because of the importance of this pathology in disease, but also for exploring potential therapeutic targets. Clinically there is a need to develop therapies to prevent or even reverse calcification in situations of atherosclerosis, chronic kidney disease, diabetes, and aging. In this brief review, we intend to explore the initial triggers, which are commonly related to calcification in different disease scenarios and examine the downstream signalling pathways that instigate the process of vascular calcification. In particular, we try to dissect these pathways and also examine cross-talk between different signalling pathways. Our focus is the vascular smooth muscle cell (VSMC) as it is ultimately the phenotypic modulation of these cells that may drive the calcification process.

Topics: Aging; Bone Morphogenetic Proteins; Calcinosis; Humans; Hypercalcemia; Hyperphosphatemia; Inflammation; Interleukin-6; Muscle, Smooth, Vascular; Oxidative Stress; Receptors, Notch; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factors; Vascular Diseases; Wnt Proteins

The phenotype of vascular smooth muscle cells (VSMCs) is dynamically regulated in response to various stimuli. In a cellular process known as phenotype switching, VSMCs alternate between a contractile and synthetic phenotype state. Deregulation of phenotype switching is associated with vascular disorders such as atherosclerosis, restenosis after angioplasty, and pulmonary hypertension. An important role for microRNAs (miRNAs) in VSMC development and phenotype switching has recently been uncovered. Individual miRNAs are involved in promoting both contractile and synthetic VSMC phenotype. In this review, we summarize recent advances in the understanding of miRNA function in the regulation of VSMC phenotype regulation.

Topics: Animals; Bone Morphogenetic Protein 4; Cell Differentiation; Disease Models, Animal; Humans; Mice; MicroRNAs; Muscle, Smooth, Vascular; Phenotype; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases

Studies of rare genetic diseases frequently reveal genes that are fundamental to life, and the familial vascular disorder HHT (hereditary haemorrhagic telangiectasia) is no exception. The majority of HHT patients are heterozygous for mutations in either the ENG (endoglin) or the ACVRL1 (activin receptor-like kinase 1) gene. Both genes are essential for angiogenesis during development and mice that are homozygous for mutations in Eng or Acvrl1 die in mid-gestation from vascular defects. Recent development of conditional mouse models in which the Eng or Acvrl1 gene can be depleted in later life have confirmed the importance of both genes in angiogenesis and in the maintenance of a normal vasculature. Endoglin protein is a co-receptor and ACVRL1 is a signalling receptor, both of which are expressed primarily in endothelial cells to regulate TGFβ (transforming growth factor β) signalling in the cardiovasculature. The role of ACVRL1 and endoglin in TGFβ signalling during angiogenesis is now becoming clearer as interactions between these receptors and additional ligands of the TGFβ superfamily, as well as synergistic relationships with other signalling pathways, are being uncovered. The present review aims to place these recent findings into the context of a better understanding of HHT and to summarize recent evidence that confirms the importance of endoglin and ACVRL1 in maintaining normal cardiovascular health.

Topics: Amino Acid Sequence; Animals; Blood Vessels; Humans; Molecular Sequence Data; Neovascularization, Physiologic; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases

The underlying pathogenesis of systemic sclerosis (SSc; scleroderma) involves a complex interplay of inflammation, fibrosis and vasculopathy that is incompletely understood. In this article, we highlight the important contributions that recent preclinical research has made to the knowledge base of pathogenesis and therapeutics in SSc, describe some of the newly developed models available for further investigation and discuss future research opportunities in this fascinating area.. Several well characterized SSc models are available for the study of fibrosis. However, recent study on transgenic and knockout models has advanced knowledge both in fibrosis research and in vascular disease in SSc. In the present review, we focus on models in which altered signalling, particularly transforming growth factor-beta (TGF-beta), is limited to fibroblasts. We discuss contemporary models of SSc vascular disease, transgenesis in fibrocyte research, the contribution to neurological signalling research and provide examples of how preclinical models have contributed to novel therapeutics development in SSc. We also look at how research from related disciplines impacts on the SSc knowledge base.. These new models represent exciting advances. However, none completely recapitulates the vasculopathic and inflammatory components of this disease. These advances help to delineate the relative contributions of specific ligands, receptors, their signalling pathways and feedback mechanisms, in fibrotic and inflammatory processes and this will provide new targets for potential therapies in SSc.

Topics: Animals; Collagen; Disease Models, Animal; Fibroblasts; Fibrosis; Hematopoietic Stem Cells; Mice; Mice, Knockout; Mice, Transgenic; Models, Biological; Neuropeptides; Platelet-Derived Growth Factor; Scleroderma, Systemic; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases

Vascular tissue engineering aims to restore blood flow by seeding artificial tubular scaffolds with endothelial and smooth muscle cells, thus creating bioartificial blood vessels. Herein, the progenitors of smooth muscle and endothelial cells hold great promise because they efficiently differentiate and harbor longevity. In this review, we describe a novel tissue engineering approach that uses current insights from developmental biology, that is, progenitor cell plasticity, and the latest advances in biomaterial design. We focus specifically on developmental processes that regulate progenitor cell (trans)differentiation and offer a platform for the integration of these molecular clues into biomaterial design. We propose a novel engineering paradigm for the creation of a small-diameter blood vessel wherein progenitor cell differentiation and tissue organization are instructed by the biomaterial solely. With this review, we emphasize the power of integrating developmental biology and material science for vascular tissue engineering.

Topics: Blood Vessel Prosthesis; Culture Techniques; Endothelium, Vascular; Humans; Mesoderm; Muscle, Smooth, Vascular; Tissue Engineering; Transforming Growth Factor beta; Vascular Diseases

In the last decade, the nephrology community has focused its attention on the main cause of morbidity and mortality in chronic renal failure patients: cardiovascular disease. In addition, recent studies pointed out that vascular calcification (VC) is a major cause of cardiovascular disease in the dialysis population. Interestingly, the pathogenesis of VC and soft tissue calcification in chronic kidney disease (CKD) has been extensively investigated. Nowadays we know that VC is associated not only with passive calcium phosphate deposition, but also with an active, cell-mediated process. To better understand the pathogenesis of VC in CKD, numerous regulatory proteins have been studied, because of their ability to inhibit mineral deposition in the vessels. We here examine the state of the art of those substances recognized as regulatory key factors in preventing VC in uremic conditions, such as fetuin A (alpha2-Heremans-Schmid glycoprotein), matrix gamma-carboxyglutamic acid protein, pyrophosphate, osteoprotegerin and bone morphogenetic protein. We conclude that at present it is too early to introduce these novel markers into clinical practice.

Topics: 1-Carboxyglutamic Acid; alpha-Fetoproteins; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcinosis; Diphosphates; Humans; Kidney Failure, Chronic; Models, Biological; Osteoprotegerin; Risk Factors; Transforming Growth Factor beta; Uremia; Vascular Diseases

Arterial calcification is common in patients with type 2 diabetes mellitus (DM), chronic kidney disease (CKD), and other chronic inflammatory disorders. Arterial calcification is associated with significant morbidity and increased early mortality. The molecular signature of vascular calcification in diabetes is strikingly similar to that of CKD. Low-grade arterial inflammation is common to both conditions, and increased levels of tumor necrosis factor-alpha (TNF-alpha) have been reported in both DM and CKD. Recently, we described a novel TNF-alpha regulated Msx2-Wnt osteogenic program that regulates arterial calcification in an animal model of type 2 DM. TNF-alpha induces the osteogenic bone morphogenetic protein-2 (BMP-2), Msx2, Wnt3a, and Wnt7a mRNAs and leads to increased aortic calcium accumulation. Treatment with the TNF-alpha neutralizing antibody infliximab abrogates aortic BMP-2-Msx2-Wnt3a and Wnt7a signaling and attenuates aortic calcium accumulation significantly. Mice with vascular TNF-alpha augmented by the SM22-TNF-alpha transgene upregulate the aortic Msx2-Wnt3a/Wnt7a axis. Furthermore, SM22-TNF-alphaTg;TOPGAL mice exhibit greater beta-galactosidase reporter staining versus TOPGAL siblings in the aorta and coronaries, which indicates enhanced mural Wnt signaling in response to TNF-alpha. Thus, inflammatory TNF-alpha signals promote aortic osteogenic Msx2-Wnt programs in type 2 DM, and arterial calcification in this model is a TNF-alpha-driven Wnt-opathy. Having established the role of TNF-alpha in diabetic vascular calcification, an unmet need exists to evaluate the role of TNF-alpha and Msx2-Wnt signals in CKD-related calcification models. If validated in these models, then these findings will have significant therapeutic applications.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Calcinosis; Gene Expression; Humans; Microfilament Proteins; Models, Biological; Muscle Proteins; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Diseases; Wnt Proteins

The intracellular mechanism of transforming growth factor-beta (TGFbeta) signalling via kinase receptors and SMAD effectors is firmly established, but recent studies of human cardiovascular syndromes such as Marfan syndrome and pre-eclampsia have refocused attention on the importance of regulating the availability of active extracellular TGFbeta. It seems that elastic extracellular matrix (ECM) components have a crucial role in controlling TGFbeta signalling, while soluble and membrane bound forms of TGFbeta co-receptors add further layers of regulation. Together, these extracellular interactions determine the final bioavailability of TGFbeta to vascular cells, and dysregulation is associated with an increasing number of vascular pathologies.

Topics: Animals; Blood Vessels; Extracellular Matrix; Humans; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases

Transforming growth factor-beta (TGF-beta) superfamily members, TGF-beta and bone morphogenetic proteins (BMPs), are potent regulatory cytokines with diverse functions on vascular cells. They signal through heteromeric type I and II receptor complexes activating Smad-dependent and Smad-independent signals, which regulate proliferation, differentiation, and survival. They are potent regulators of vascular development and vessel remodeling and play key roles in atherosclerosis and restenosis, regulating endothelial, smooth muscle cell, macrophage, T cell, and probably vascular calcifying cell responses. In atherosclerosis, TGF-beta regulates lesion phenotype by controlling T-cell responses and stimulating smooth muscle cells to produce collagen. It contributes to restenosis by augmenting neointimal cell proliferation and collagen accumulation. Defective TGF-beta signaling in endothelial cells attributable to mutations in endoglin or the type I receptor ALK-1 leads to hereditary hemorrhagic telangiectasia, whereas defective BMP signaling attributable to mutations in the BMP receptor II has been associated with development of primary pulmonary hypertension. The development of mouse models with either cell type-specific or general inactivation of TGF-beta/BMP signaling has started to reveal the importance of the regulatory network of TGF-beta/BMP pathways in vivo and their significance for atherosclerosis, hereditary hemorrhagic telangiectasia, and primary pulmonary hypertension. This review highlights recent findings that have advanced our understanding of the roles of TGF-beta superfamily members in regulating vascular cell responses and provides likely avenues for future research that may lead to novel pharmacological therapies for the treatment or prevention of vascular disorders.

Topics: Animals; Humans; Mutation; Transforming Growth Factor beta; Vascular Diseases

Transforming growth factor (TGF)-beta is a multifunctional cytokine involved in the regulation of proliferation, differentiation, migration, and survival of many different cell types. The role of TGF-beta in atherosclerosis has been intensively studied, but the precise function of the downstream signals in this disease entity remains unclear. We recently discovered that mice lacking Smad3, a major downstream mediator of TGF-beta, show enhanced neointimal hyperplasia with decreased matrix deposition in response to vascular injury. This review summarizes the current view on involvement of TGF-beta in atherosclerotic vascular disease and discusses the role of Smad3-dependent TGF-beta signal in vascular response to injury.

Topics: Animals; Homeostasis; Humans; Hyperplasia; Matrix Metalloproteinases; Myocytes, Smooth Muscle; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Tunica Intima; Vascular Diseases

Transforming growth factor (TGF)-beta is a multifunctional protein that initiates its diverse cellular responses by binding to and activating specific type I and type II serine/threonine kinase receptors. TGF-beta can act as a regulator of proliferation, migration, survival, differentiation, and extracellular matrix synthesis in endothelial cells and vascular smooth muscle cells, as well as in the maintenance of vascular homeostasis. Importantly, genetic studies in humans have revealed the pivotal role of TGF-beta as well as its signaling components in angiogenesis. Mutations in two TGF-beta receptors (ie, the activin receptor-like kinase (ALK) 1 and the accessory TGF-beta receptor endoglin) have been linked to vascular disorders named hereditary hemorrhagic telangiectasia. In addition, knockout mice for the different components of the TGF-beta signaling pathway have shown that TGF-beta is indispensable for angiogenesis. Recent studies have revealed that TGF-beta can regulate vascular homeostasis by balancing the signaling between two distinct TGF-beta type I receptors (ie, the endothelial-restricted ALK1 and the broadly expressed ALK5 receptors). The activation of these receptors has been shown to induce opposite effects on endothelial cell behavior and angiogenesis. In this review, we will present recent advances in understanding the role of TGF-beta signaling in endothelial cells as well as the underlying molecular mechanisms by which perturbation of this pathway can lead to vascular disorders.

Topics: Animals; Humans; Mice; Mice, Knockout; Neovascularization, Physiologic; Signal Transduction; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta; Vascular Diseases

When last reviewed, bone morphogenetic protein 7 was presented as a potential new renal therapeutic agent, with multiple efficacies in chronic kidney disease. The object of this review is to describe progress from many sources since then in support or denial of the hypothesis.. Bone morphogenetic protein 7 has been shown to be an effective defence in several forms of chronic kidney disease in animal models, and its mechanisms of action have begun to be elucidated. Bone morphogenetic protein 7 inhibits tubular epithelial cell de-differentiation, mesenchymal transformation and apoptosis stimulated by various renal injuries. Bone morphogenetic protein 7 preserves glomerular integrity and inhibits injury-mediated mesangial matrix accumulation. In renal osteodystrophy, bone morphogenetic protein 7 affects osteoblast morphology and number, eliminates peritrabecular fibrosis, decreases bone resorption, and increases bone formation in secondary hyperparathyroidism. Bone morphogenetic protein 7 restores normal rates of bone formation in the adynamic bone disorder. Bone morphogenetic protein 7 is broadly efficacious in renal osteodystrophy, and importantly increases the skeletal deposition of ingested phosphorus and calcium, improving ion homeostasis in chronic kidney disease. Bone morphogenetic protein 7 was shown to prevent vascular calcification in a model of chronic kidney disease associated with the restoration of osteocalcin expression to normal tissue-restricted sites.. Bone morphogenetic protein 7 may be a powerful new therapeutic agent for chronic kidney disease, with the novel attribute of not only treating the kidney disease itself, but also directly inhibiting some of the most important complications of the disease state.

Topics: Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcinosis; Chronic Kidney Disease-Mineral and Bone Disorder; Diabetic Nephropathies; Fibrosis; Humans; Kidney Diseases; Kidney Failure, Chronic; Lupus Nephritis; Nephritis, Hereditary; Transforming Growth Factor beta; Vascular Diseases

Vascular calcification is a pathological calcification process. Its pathogenesis involves active mineralization by chondrogenic and osteogenic cells. Since cartilaginous metaplasia has been found in several vascular diseases, this process may represent one of vascular remodeling in response to vascular injury. Endochondral ossification following cartilaginous metaplasia play an important role in the progression of vascular calcification.

Topics: Animals; Arteriosclerosis; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Calcinosis; Cell Differentiation; Chondrocytes; Chondrogenesis; Collagen Type II; Cytokines; Diabetes Complications; High Mobility Group Proteins; Humans; Metaplasia; Muscle, Smooth, Vascular; Neoplasm Proteins; SOX9 Transcription Factor; Transcription Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vascular Diseases

Vascular calcification in dialysis patients is associated with morbidity and mortality risks. Recent evidence suggests that vascular calcification is an active process resembling osteogenesis and chondrogenesis process. In this process, hyperphosphatemia is one of the important regulators. Inorganic phosphates directly regulate vascular calcification in vitro through a sodium-dependent phosphate cotransporter and promote expression of the osteoblastic differentiation markers.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Calcinosis; Calcium-Binding Proteins; Dialysis; Extracellular Matrix Proteins; Humans; Matrix Gla Protein; Neoplasm Proteins; Osteopontin; Phosphorus; Phosphorus Metabolism Disorders; Risk; Sialoglycoproteins; Sodium-Phosphate Cotransporter Proteins; Symporters; Transcription Factors; Transforming Growth Factor beta; Vascular Diseases

The transforming growth factor-beta (TGF-beta) superfamily includes more than 30 members which have a broad array of biological activities. TGF-beta superfamily ligands bind to type II and type I serine/threonine kinase receptors and transduce signals via Smad proteins. Receptor-regulated Smads (R-Smads) can be classified into two subclasses, i.e. those activated by activin and TGF-beta signaling pathways (AR-Smads), and those activated by bone morphogenetic protein (BMP) pathways (BR-Smads). The numbers of type II and type I receptors and Smad proteins are limited. Thus, signaling of the TGF-beta superfamily converges at the receptor and Smad levels. In the intracellular signaling pathways, Smads interact with various partner proteins and thereby exhibit a wide variety of biological activities. Moreover, signaling by Smads is modulated by various other signaling pathways allowing TGF-beta superfamily ligands to elicit diverse effects on target cells. Perturbations of the TGF-beta/BMP signaling pathways result in various clinical disorders including cancers, vascular diseases, and bone disorders.

Topics: Animals; Bone Morphogenetic Proteins; DNA-Binding Proteins; Humans; Hypertension, Pulmonary; Ligands; Mice; Multigene Family; Protein Serine-Threonine Kinases; Receptors, Growth Factor; Receptors, Transforming Growth Factor beta; Signal Transduction; Trans-Activators; Transforming Growth Factor beta; Vascular Diseases

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression; Hemostasis; Humans; Mice; Obesity; Plasminogen Activator Inhibitor 1; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Diseases

Genetic studies have recently revealed a role for transforming growth factor-beta-1 (TGF-beta 1) and its receptors (TGF-beta Rs I and II as well as endoglin) in embryonic vascular assembly and in the establishment and maintenance of vessel wall integrity. The purpose of this review is threefold: first, to reassess previous studies on TGF-beta and endothelium in the light of these recent findings; second, to describe some of the well-established as well as controversial issues concerning TGF-beta and its regulatory role in angiogenesis; and third, to explore the notion of "context' with respect to TGF-beta and endothelial cell function. Although the focus of this review will be on the endothelium, other vascular wall cells are also likely to be important in the pathogenesis of the vascular lesions revealed by genetic studies.

Topics: Animals; Blood Vessels; Endothelium, Vascular; Gene Expression Regulation, Developmental; Gene Targeting; Humans; In Vitro Techniques; Neovascularization, Physiologic; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta; Vascular Diseases

Topics: Biomechanical Phenomena; Cell Adhesion; Chemokine CCL2; Endothelin-1; Endothelins; Endothelium, Vascular; Humans; Inflammation Mediators; Intercellular Adhesion Molecule-1; Platelet-Derived Growth Factor; Protein Precursors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-sis; Thromboplastin; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1; Vascular Diseases

Endothelial-to-mesenchymal transition (EndMT), a process initiated by activation of endothelial TGF-β signaling, underlies numerous chronic vascular diseases and fibrotic states. Once induced, EndMT leads to a further increase in TGF-β signaling, thus establishing a positive-feedback loop with EndMT leading to more EndMT. Although EndMT is understood at the cellular level, the molecular basis of TGF-β-driven EndMT induction and persistence remains largely unknown. Here, we show that metabolic modulation of the endothelium, triggered by atypical production of acetate from glucose, underlies TGF-β-driven EndMT. Induction of EndMT suppresses the expression of the enzyme PDK4, which leads to an increase in ACSS2-dependent Ac-CoA synthesis from pyruvate-derived acetate. This increased Ac-CoA production results in acetylation of the TGF-β receptor ALK5 and SMADs 2 and 4 leading to activation and long-term stabilization of TGF-β signaling. Our results establish the metabolic basis of EndMT persistence and unveil novel targets, such as ACSS2, for the potential treatment of chronic vascular diseases.

Topics: Endothelial Cells; Endothelium; Humans; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases

As a crucial regulatory molecule in the context of vascular stenosis, transforming growth factor-β (TGF-β), plays a pivotal role in its initiation and progression. TGF-β, a member of the TGF-β superfamily, can bind to the TGF-β receptor and transduce extracellular to intracellular signals through canonical Smad dependent or noncanonical signaling pathways to regulate cell growth, proliferation, differentiation, and apoptosis. Restenosis remains one of the most challenging problems in cardiac, cerebral, and peripheral vascular disease worldwide. The mechanisms for occurrence and development of restenosis are diverse and complex. The TGF-β pathway exhibits diversity across various cell types. Hence, clarifying the specific roles of TGF-β within different cell types and its precise impact on vascular stenosis provides strategies for future research in the field of stenosis.. 转化生长因子β(transforming growth factor-β，TGF-β)是血管再狭窄中重要的调控分子，在血管再狭窄的发生、发展中发挥关键作用。TGF-β是TGF-β超家族成员之一，可与TGF-β受体相结合，通过经典的依赖Smad蛋白通路或非经典通路将膜外信号转导到膜内，从而调控细胞的生长、增殖、分化和凋亡的过程。血管再狭窄至今仍是心脑及外周血管疾病中难以攻克的世界性难题之一，其发生、发展机制具有多样性和复杂性。预防术后血管再狭窄或延长血管通畅时间具有重要的临床意义。TGF-β通路在不同细胞类型中表现出多样性，探讨TGF-β在不同细胞类型中的作用及其对血管再狭窄的具体影响有助于为TGF-β与血管再狭窄的相关研究提供依据和策略。.

Topics: Cell Differentiation; Constriction, Pathologic; Humans; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factors; Vascular Diseases

Endothelial dysfunction (ED) is a key factor for the development of cardiovascular diseases. Due to its chronic, life-threatening nature, ED only can be studied experimentally in animal models. Therefore, this work was aimed to characterize a murine model of ED induced by a daily intraperitoneal administration of angiotensin II (AGII) for 10 weeks. Oxidative stress, inflammation, vascular remodeling, hypertension, and damage to various target organs were evaluated in treated animals. The results indicated that a chronic intraperitoneal administration of AGII increases the production of systemic soluble VCAM, ROS and ICAM-1 expression, and the production of TNFα, IL1β, IL17A, IL4, TGFβ, and IL10 in the kidney, as well as blood pressure levels; it also promotes vascular remodeling and induces non-alcoholic fatty liver disease, glomerulosclerosis, and proliferative retinopathy. Therefore, the model herein proposed can be a representative model for ED; additionally, it is easy to implement, safe, rapid, and inexpensive.

Topics: Angiotensin II; Animals; Disease Models, Animal; Endothelium, Vascular; Infusions, Parenteral; Intercellular Adhesion Molecule-1; Interleukins; Kidney; Liver; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vascular Remodeling

[Figure: see text].

Topics: Apoptosis; Arterioles; Child; Cytoskeleton; Endothelial Cells; Glucose; Humans; Interleukin-6; Lamins; Peritoneal Dialysis; Peritoneum; Renal Insufficiency, Chronic; Smad Proteins; Tight Junctions; Transforming Growth Factor beta; Vascular Diseases

Systemic sclerosis is a multisystem inflammatory and vascular lesion leading to extensive tissue fibrosis. A reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, DZ2002, modulates the pathologic processes of various inflammatory diseases and autoimmune diseases. This study is designed to investigate the therapeutic potentiality of DZ2002 for experimental systemic sclerosis models.. The anti-inflammatory and anti-fibrotic features of DZ2002 and its mechanisms were investigated in a bleomycin (BLM)-induced dermal fibrosis mice model. The effects of DZ2002 on expression of extracellular matrix components and TGF-β signaling in human dermal fibroblasts were analyzed. Simultaneously, the effects of DZ2002 on macrophage activation and endothelial cell adhesion molecule expression were also evaluated.. DZ2002 significantly attenuated dermal fibrosis in BLM-induced mice. Consistently, DZ2002 inhibited the expression of various molecules associated with dermal fibrosis, including transforming growth factor β1, connective tissue growth factor, tumor necrosis factor-α, interferon-γ, IL-1β, IL-4, IL-6, IL-10, IL-12p40, IL-17A, and monocyte chemotactic protein 1 in the lesional skin of BLM-induced mice. Furthermore, DZ2002 decreased the proportion of macrophages, neutrophils, and T cells (especially T helper cells) in the skin tissue of BLM-induced mice. In addition, DZ2002 attenuated both M1 macrophage and M2 macrophage differentiation in vivo and in vitro. Importantly, DZ2002 directly reversed the profibrotic phenotype of transforming growth factor-β1-treated dermal fibroblasts and suppressed ICAM-1, VCAM-1, VEGF, bFGF, and ET-1 expression in endothelial cells. Finally, our investigations showed that DZ2002 relieved systemic sclerosis by regulating fibrosis TGF-β/Smad signaling pathway.. DZ2002 prevents the development of experimental dermal fibrosis by reversing the profibrotic phenotype of various cell types and would be a potential drug for the treatment of systemic sclerosis.

Topics: Adenine; Animals; Bleomycin; Butyrates; Cell Line; Cells, Cultured; Dermis; Disease Models, Animal; Female; Fibroblasts; Fibrosis; Gene Expression; Humans; Inflammation; Macrophages; Mice, Inbred C57BL; Scleroderma, Systemic; THP-1 Cells; Transforming Growth Factor beta; Vascular Diseases; Vascular Endothelial Growth Factor A

Systemic sclerosis (SSc) is a multisystem inflammatory and vascular disease resulting in extensive tissue fibrosis. Glycyrrhizin, clinically used for chronic hepatic diseases and itching dermatitis, modulates the pathological processes of inflammation, vasculopathy, and fibrosis in human diseases and their animal models. Therefore, we investigated a potential impact of glycyrrhizin on the key pathological manifestations of SSc, including inflammation, vasculopathy, and tissue fibrosis, with bleomycin-treated mice mimicking the fibrotic and inflammatory components of SSc and endothelial cell-specific Fli1-knockout mice recapitulating SSc vasculopathy. Glycyrrhizin significantly ameliorated dermal fibrosis in bleomycin-treated mice, which was partly attributable to blockade of transforming growth factor-β signaling in dermal fibroblasts through the down-regulation of thrombospondin 1, a latent transforming growth factor-β receptor, and transcription factors Smad3 and Ets1. Furthermore, bleomycin-dependent induction of T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition were greatly suppressed in mice administered glycyrrhizin. Glycyrrhizin also improved vascular permeability of endothelial cell-specific Fli1-knockout mice by increasing the expression of molecules regulating vascular integrity. These results indicate that glycyrrhizin ameliorates bleomycin-induced dermal fibrosis through the inhibition of fibroblast activation, T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition and improves endothelial Fli1 deficiency-dependent vascular disintegrity, implying its potential as a disease-modifying drug for SSc.

Topics: Animals; Bleomycin; Disease Models, Animal; Fibroblasts; Fibrosis; Glycyrrhizic Acid; Humans; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Scleroderma, Systemic; Skin; Th2 Cells; Transforming Growth Factor beta; Vascular Diseases

The efficacy and feasibility of targeting transforming growth factor-β (TGFβ) in pulmonary fibrosis and lung vascular remodeling in systemic sclerosis (SSc) have not been well elucidated. In this study we analyzed how blocking TGFβ signaling affects pulmonary abnormalities in Fos-related antigen 2 (Fra-2) transgenic (Tg) mice, a murine model that manifests three important lung pathological features of SSc: fibrosis, inflammation, and vascular remodeling. To interrupt TGFβ signaling in the Fra-2 Tg mice, we used a pan-TGFβ-blocking antibody, 1D11, and Tg mice in which TGFβ receptor type 2 (Tgfbr2) is deleted from smooth muscle cells and myofibroblasts (α-SMA-Cre

Topics: Actins; Animals; Bone Morphogenetic Protein Receptors, Type II; Disease Models, Animal; Fos-Related Antigen-2; Gene Deletion; Granulocytes; Mice, Transgenic; Myocytes, Smooth Muscle; Pneumonia; Protein Serine-Threonine Kinases; Pulmonary Alveoli; Pulmonary Fibrosis; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Scleroderma, Systemic; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases; Vascular Remodeling

Although the relationship between atherosclerosis and overt hypothyroidism has been confirmed, it remains controversial in cases of subclinical hypothyroidism. Higher TSH and similar T4 suggest differences in set-points or differences due to diagnostic limitations regarding subclinical hypothyroidism. Endothelial dysfunction (ED) is a marker rather than a precursor of cardiovascular disease. Asymmetric dimethylarginine (ADMA) and endocan are known as novel markers of ED in various diseases. Transforming growth factor-beta (TGF-β) has a protective role against autoimmune diseases such as thyroiditis. This study aimed to determine the relationships between serum ADMA, endocan, TGF-β, and the high-sensitivity C-reactive protein (hs-CRP) levels, a proven indicator of ED, in patients with SH.. Thirty-five patients with SH and 21 age- and sex-matched euthyroid subjects were included in the study. The levels of TSH, FT4, lipid parameters, endocan, ADMA, TGF-β, and hs-CRP were measured.. No significant differences in age or sex were found between the patient and control groups (p=0.294 and 0.881, respectively). Mean TSH level was higher in the patient group (p=0.005), whereas mean fT4 level was similar in two groups (p=0.455). The average hs-CRP, endocan, TGF-β l level in the patient group was higher than control group (p=0.001; P=0.012; P=0.025; P<0.01 respectively). A positive correlation was found between the endocan and ADMA levels (r=0.760, p=0.000). ADMA levels also were positively correlated with hs-CRP. Both the TSH and low-density lipoprotein cholesterol (LDL-C) levels were positively correlated with the hs-CRP level.. Subclinical hypothyroidism is associated with increased levels of serum endocan, ADMA, and TGF-β, which are new markers for ED. In particular, ADMA was correlated with both endocan and hs-CRP levels. These findings are suggestive for increased risk of ED and subsequent development of atherosclerosis in patients with SH.

Topics: Adult; Arginine; Biomarkers; Demography; Endothelium, Vascular; Female; Humans; Hypothyroidism; Inflammation; Male; Neoplasm Proteins; Proteoglycans; Risk Factors; Thyroid Function Tests; Transforming Growth Factor beta; Vascular Diseases

Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal failure that is due to mutations in two genes, PKD1 and PKD2. Vascular complications, including aneurysms, are a well recognized feature of ADPKD, and a subgroup of families exhibits traits reminiscent of Marfan syndrome (MFS). MFS is caused by mutations in fibrillin-1 (FBN1), which encodes an extracellular matrix protein with homology to latent TGF-β binding proteins. It was recently demonstrated that fibrillin-1 deficiency is associated with upregulation of TGF-β signaling. We investigated the overlap between ADPKD and MFS by breeding mice with targeted mutations in Pkd1 and Fbn1. Double heterozygotes displayed an exacerbation of the typical Fbn1 heterozygous aortic phenotype. We show that the basis of this genetic interaction results from further upregulation of TGF-β signaling caused by Pkd1 haploinsufficiency. In addition, we demonstrate that loss of PKD1 alone is sufficient to induce a heightened responsiveness to TGF-β. Our data link the interaction of two important diseases to a fundamental signaling pathway.

Topics: Animals; Disease Models, Animal; Epistasis, Genetic; Female; Fibrillin-1; Fibrillins; Genetic Association Studies; Haploinsufficiency; Heterozygote; Humans; Male; Marfan Syndrome; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Microfilament Proteins; Mutation; Polycystic Kidney, Autosomal Dominant; Signal Transduction; Transforming Growth Factor beta; TRPP Cation Channels; Vascular Diseases

Topics: Animals; Female; Humans; Male; Microfilament Proteins; Polycystic Kidney, Autosomal Dominant; Transforming Growth Factor beta; TRPP Cation Channels; Vascular Diseases

Cathepsin B (CTSB) is a proteolytic enzyme potentially modulating angiogenic processes and extracellular matrix remodeling. While matrix metalloproteinases are shown to be implicated in tissue fibrosis and vasculopathy associated with systemic sclerosis (SSc), the role of cathepsins in this disease has not been well studied. The aim of this study is to evaluate the roles of CTSB in SSc. Serum pro-CTSB levels were determined by enzyme-linked immunosorbent assay in 55 SSc patients and 19 normal controls. Since the deficiency of transcription factor Fli1 in endothelial cells is potentially associated with the development of SSc vasculopathy, cutaneous CTSB expression was evaluated by immunostaining in Fli1(+/-) and wild type mice as well as in SSc and control subjects. The effects of Fli1 gene silencing and transforming growth factor-β (TGF-β) on CTSB expression were determined by real-time PCR in human dermal microvascular endothelial cells (HDMECs) and dermal fibroblasts, respectively. Serum pro-CTSB levels were significantly higher in limited cutaneous SSc (lcSSc) and late-stage diffuse cutaneous SSc (dcSSc) patients than in healthy controls. In dcSSc, patients with increased serum pro-CTSB levels showed a significantly higher frequency of digital ulcers than those with normal levels. CTSB expression in dermal blood vessels was increased in Fli1(+/-) mice compared with wild type mice and in SSc patients compared with healthy controls. Consistently, Fli1 gene silencing increased CTSB expression in HDMECs. In cultured dermal fibroblasts from early dcSSc, CTSB expression was decreased compared with normal fibroblasts and significantly reversed by TGF-β1 antisense oligonucleotide. In conclusion, up-regulation of endothelial CTSB due to Fli1 deficiency may contribute to the development of SSc vasculopathy, especially digital ulcers, while reduced expression of CTSB in lesional dermal fibroblasts is likely to be associated with skin sclerosis in early dcSSc.

Topics: Animals; Case-Control Studies; Cathepsin B; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Female; Gene Silencing; Humans; Male; Mice; Microcirculation; Scleroderma, Systemic; Skin; Transforming Growth Factor beta; Vascular Diseases

Human Cardiac Allograft Vasculopathy (CAV) is one of the major complications for patients after heart transplantation. It is characterized by a concentric luminal narrowing due to (neo) intimal expansion in the coronary arteries of donor hearts after heart transplantation. In this process fibrosis plays an important role. Aim of this study is to analyze the factors and cells involved in this fibrotic process. Coronary arteries from five heart transplantation patients and three controls were obtained at autopsy. Quantitative real-time PCR was performed on mRNA obtained from various arterial layers isolated by laser micro dissection. Positive gene expression was confirmed by immunohistochemistry and/or in situ hybridisation. The strongest mRNA expression of fibrotic factors (predominantly pro-fibrotic) was found in the neo-intima. Especially, connective tissue growth factor expression was higher in the CAV vessels than in the controls. The lymphocyte activity of interferon gamma was only detected in CAV vessels. Furthermore as shown by in situ hybridisation, the lymphocytes producing interferon gamma also expressed transforming growth factor beta. Anti-fibrotic factors, such as bone morphogenic protein 4, were only expressed in CD3(-)/CD68(-) stromal cells. Macrophages present in the CAV and control vessels showed to be of the M2 type and did not produce any fibrotic factor(s). In conclusion, T-cells producing both interferon gamma and transforming growth factor beta, may play an important role in the fibrotic process in CAV vessels by upregulation of connective tissue growth factor production.

Topics: Adolescent; Bone Morphogenetic Protein 4; Female; Fibrosis; Heart Transplantation; Humans; Interferon-gamma; Macrophages; Male; Middle Aged; Muscle, Smooth, Vascular; RNA, Messenger; Stromal Cells; T-Lymphocytes; Transforming Growth Factor beta; Transplantation, Homologous; Tunica Intima; Vascular Diseases

Tissue fibrosis and vascular disease are hallmarks of systemic sclerosis (SSc). Transforming growth factor beta (TGFbeta) is a key-player in fibroblast activation and tissue fibrosis in SSc. In contrast to fibrosis, evidence for a role of TGFbeta in vascular disease of SSc is scarce. Using a transgenic mouse model with fibroblast-specific expression of a kinase-deficient TGFbeta receptor type II, Derrett-Smith and colleagues demonstrate that aberrant TGFbeta signaling in fibroblasts might result in activation of vascular smooth muscle cells and architectural changes of the vessel wall of the aorta.

Topics: Animals; Aorta; Disease Models, Animal; Fibroblasts; Mice; Mice, Transgenic; Muscle, Smooth, Vascular; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Scleroderma, Systemic; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Aneurysm, Ruptured; Aortic Dissection; Celiprolol; Ehlers-Danlos Syndrome; Humans; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases

Vascular calcification often occurs with advancing age, atherosclerosis, and metabolic disorders such as diabetes mellitus and end-stage renal disease. Vascular calcification is associated with cardiovascular events and increased mortality. Nitric oxide (NO) is crucial for maintaining vascular function, but little is known about how NO affects vascular calcification. The aim of this study was to examine the effect of NO on vascular calcification.. In this study, we examined the inhibitory effects of NO on calcification of murine vascular smooth muscle cells (VSMCs) in vitro. We measured calcium concentration, alizarin red staining, and alkaline phosphatase activity to examine the effect of NO on calcification of VSMCs and differentiation of VSMCs into osteoblastic cells. We also determined gene expression and levels of phosphorylation of Smad2/3 by RT-PCR and western blotting. NO inhibited calcification of VSMCs and differentiation of VSMCs into osteoblastic cells. An inhibitor of cyclic guanosine monophosphate (cGMP)-dependent protein kinase restored the inhibition by NO of osteoblastic differentiation and calcification of VSMCs. NO inhibited transforming growth factor-beta (TGF-beta)-induced phosphorylation of Smad2/3 and expression of TGF-beta-induced genes such as plasminogen activator inhibitor-1. In addition, NO inhibited expression of the TGF-beta receptor ALK5.. Our data show that NO prevents differentiation of VSMCs into osteoblastic cells by inhibiting TGF-beta signalling through a cGMP-dependent pathway. Our findings suggest that NO may play a beneficial role in atherogenesis in part by limiting vascular calcification.

Topics: Animals; Calcinosis; Cell Differentiation; Cells, Cultured; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Nitric Oxide; Osteoblasts; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases

Isolated systolic hypertension is associated with increased elastase activity, vascular calcification, and vascular stiffness. We sought to determine the importance of elastase activity and matrix degradation in the development of elastocalcinosis.. Elastocalcinosis was induced in vivo and ex vivo using warfarin. Hemodynamic parameters, calcium deposition, elastin degradation, transforming growth factor (TGF)-beta signaling, and elastase activity were evaluated at different time points in the in vivo model. Metalloproteinases, serine proteases, and cysteine proteases were blocked to measure their relative implication in elastin degradation. Gradual elastocalcinosis was obtained, and paralleled the elastin degradation pattern. Matrix metalloproteinase (MMP)-9 activity was increased at 5 days of warfarin treatment, whereas TGF-beta signaling was increased at 7 days. Calcification was significantly elevated after 21 days. Blocking metalloproteinases activation with doxycycline and TGF-beta signaling with SB-431542 were able to prevent calcification.. Early MMP-9 activation precedes the increase of TGF-beta signaling, and overt vascular elastocalcinosis and stiffness. Modulation of matrix degradation could represent a novel therapeutic avenue to prevent the gradual age-related stiffening of large arteries, leading to isolated systolic hypertension.

Topics: Animals; Aorta, Abdominal; Calcinosis; Collagen; Disease Models, Animal; Durapatite; Elastin; Femoral Artery; Male; Matrix Metalloproteinase 9; Osteopontin; Rats; Rats, Wistar; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases; Warfarin

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Calcinosis; Cell Differentiation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Osteoblasts; Transforming Growth Factor beta; Vascular Diseases

Clinical studies demonstrate that mineralocorticoid receptor (MR) antagonism improves outcomes in cardiovascular patients and that vascular calcification correlates with adverse cardiac events. We have recently demonstrated that human vascular smooth muscle cells (VSMCs) express functional MRs that, in response to aldosterone, modulate expression of osteogenic genes including alkaline phosphatase (ALP) and bone morphogenetic protein-2 (BMP2). This study examines the effects of MR activation by aldosterone on the process of in vitro vascular calcification.. Using immunoblotting and adenoviral promoter-reporter assays, we demonstrated that calcifying vascular cells (CVCs), an in vitro model of vascular calcification, express MRs that mediate both aldosterone- and cortisol-stimulated gene transcription. In this model, aldosterone stimulated ALP activity, an early marker of osteoblastic differentiation, as well as mineralization. Aldosterone antagonism with spironolactone abolished both effects implicating CVC MRs in the mechanism of aldosterone-stimulated vascular calcification. Inhibition of BMP2 signaling by overexpression of dominant negative BMP2 receptor did not attenuate aldosterone-induced osteoblastic differentiation.. Aldosterone activation of MR promotes osteoblastic differentiation and mineralization of VSMCs independent of BMP2 signaling. These data provide a mechanistic link between hormone-mediated VSMC MR activation and vascular calcification, two processes associated with increased risk of cardiovascular ischemic events in humans.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Adrenal Cortex Hormones; Aldosterone; Alkaline Phosphatase; Animals; Aorta; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Calcinosis; Cattle; Cells, Cultured; Coronary Vessels; Humans; Minerals; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Receptors, Mineralocorticoid; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases

This paper was aimed to study biomarkers of endothelial injury in chronic kidney diseases. Fifty chronic kidney disease patients were subject to the following determinations: (i) circulating endothelial cells, (ii) soluble VCAM-1, (iii) transforming growth factor beta (TGFB), and (iv) intrarenal hemodynamics. Increased number of circulating endothelial cells was significantly observed. A significant depletion of vascular endothelial growth factor (VEGF) or a depleted VEGF/TGFB ratio was also documented. Results showed that sVCAM was not significantly different from normal control. Intrarenal hemodynamic alteration demonstrated a characteristic of hemodynamic maladjustment. Since increased number of circulating endothelial cells is a sensitive biomarker for endothelial cell injury in chronic kidney diseases, such injury is supported by the depletion of VEGF. The endothelial cell loss correlates with the glomerular endothelial dysfunction characterized by hemodynamic maladjustment at the efferent arteriole and reduction in peritubular capillary flow. In conclusion, correction of such hemodynamic maladjustment with multidrug vasodilators can effectively restore renal function in chronic kidney diseases.

Topics: Biomarkers; Case-Control Studies; Chronic Disease; Endothelial Cells; Hemodynamics; Humans; Kidney Diseases; Microcirculation; Renal Circulation; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1; Vascular Diseases

Topics: Glucose; Monosaccharide Transport Proteins; Mutation; Transforming Growth Factor beta; Vascular Diseases

In two independent and separate studies, we have shown that renal injury and chronic kidney disease (CKD) directly inhibit skeletal anabolism, and that stimulation of bone formation decreased the serum phosphate. In the first study, the serum Ca PO(4), parathyroid hormone (PTH), and calcitriol were maintained normal after renal ablation in mice, and even mild renal injury equivalent to stage 3 CKD decreased bone formation rates. More recently, these observations were rediscovered in low-density lipoprotein receptor null (LDLR-/-) mice fed high-fat/cholesterol diets, a model of the metabolic syndrome (hypertension, obesity, dyslipidemia and insulin resistance). We demonstrated that these mice have vascular calcification (VC) of both the intimal atherosclerotic type and medial calcification. We have also shown that VC is made worse by CKD and ameliorated by bone morphogenetic protein-7 (BMP-7). The finding that high-fat fed LDLR-/- animals with CKD had hyperphosphatemia which was prevented in BMP-7-treated animals lead us to examine the skeletons of these mice. It was found that significant reductions in bone formation rates were associated with high-fat feeding, and superimposing CKD resulted in the adynamic bone disorder (ABD), while VC was made worse. The effect of CKD to decrease skeletal anabolism (decreased bone formation rates and reduced number of bone modelling units) occurred despite secondary hyperparathyroidism. The BMP-7 treatment corrected the ABD and hyperphosphatemia, owing to BMP-7-driven stimulation of skeletal phosphate deposition reducing plasma phosphate and thereby removing a major stimulus to VC. A pathological link between abnormal bone mineralization and VC through the serum phosphorus was demonstrated by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. Thus, in the metabolic syndrome with CKD, a reduction in bone forming potential of osteogenic cells leads to the ABD producing hyperphosphatemia and VC, processes ameliorated by BMP-7, in part through increased bone formation and skeletal deposition of phosphate and in part through direct actions on vascular smooth muscle cells. We have demonstrated that the processes leading to vascular calcification begin with even mild levels of renal injury affecting the skeleton before demonstrable hyperphosphatemia and that they are preventable and treatable. Therefore, early intervention in the skeletal disorder associated wi

Topics: Animals; Bone and Bones; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcinosis; Cartilage; Cell Differentiation; Chronic Kidney Disease-Mineral and Bone Disorder; Humans; Kidney; Kidney Failure, Chronic; Mice; Osteoblasts; Osteogenesis; Phosphates; Transforming Growth Factor beta; Vascular Diseases

Damage to vessels is one of the most common effects of therapeutic irradiation on normal tissues. We undertook a study in patients treated with preoperative radiotherapy and demonstrated in vivo the importance of proliferation, migration, and fibrogenic phenotype of vascular smooth muscle cells (VSMCs) in radiation-induced vascular damage. These lesions may result from imbalance in the cross talk between endothelial cells (ECs) and VSMCs. Using co-culture models, we examined whether ECs influence proliferation, migration, and fibrogenic phenotype of VSMCs. In the presence of irradiated ECs, proliferation and migration of VSMCs were increased. Moreover, expressions of alpha-smooth muscle actin, connective tissue growth factor, plasminogen activator inhibitor type 1, heat shock protein 27, and collagen type III, alpha 1 were up-regulated in VSMCs exposed to irradiated ECs. Secretion of transforming growth factor (TGF)-beta1 was increased after irradiation of ECs, and irradiated ECs activated the Smad pathway in VSMCs by inducing Smad3/4 nuclear translocation and Smad-dependent promoter activation. Using small interferring RNA targeting Smad3 and a TGFbeta-RII neutralizing antibody, we demonstrate that a TGF-beta1/TGF-beta-RII/Smad3 pathway is involved in the fibrogenic phenotype of VSMCs induced by irradiated ECs. In conclusion, we show the importance of proliferation, migration, and fibrogenic phenotype of VSMCs in patients. Moreover, we demonstrate in vitro that ECs influence these fundamental mechanisms involved in radiation-induced vascular damages.

Topics: Actins; Adenocarcinoma; Cell Movement; Cell Proliferation; Coculture Techniques; Collagen Type I; Collagen Type III; Connective Tissue Growth Factor; Endothelium, Vascular; Fibrinogen; Gamma Rays; Heat-Shock Proteins; Humans; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Plasminogen Activator Inhibitor 1; Radiation Injuries; Rectal Neoplasms; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta; Up-Regulation; Vascular Diseases

Vascular calcification is common in diabetes but the pathogenesis is poorly understood.. To investigate the pathogenesis, we first examined the histology of inferior epigastric arteries from diabetic and non-diabetic patients undergoing a renal transplant. To examine the role of hyperglycaemia, bovine vascular smooth muscle cells (BVSMCs) were incubated with normal (5 mM) or high glucose (25 mM) for 48 or 72 h.. The results demonstrated that diabetic patients, compared with non-diabetic patients, had significantly greater calcification and increased expression of the bone matrix proteins osteopontin, type I collagen, bone sialoprotein and alkaline phosphatase (ALP). The in vitro studies demonstrated that high glucose increased the expression of the osteoblast transcription factor core binding factor alpha subunit 1 (Cbfa1) and its downstream protein osteocalcin by 1.9-fold and 1.8-fold, respectively, and ALP activity by 1.5-fold. These findings were blunted in the presence of an inhibitor to protein kinase C. High glucose also significantly enhanced calcification in BVSMC in a time-dependent manner (2.20 +/- 0.50 vs 1.35 +/- 0.55 micromol/mg, day 7; 5.04 +/- 1.35 vs 3.12 +/- 0.92 micromol/mg, day 14; P < 0.05). High glucose also induced the secretion of bone morphogenetic protein-2, a known osteoinductive factor, and further increased the secretion normally seen during calcification by 43% at day 7 and 57% at day 14.. These results demonstrate that vascular calcification in patients with diabetes is a cell-mediated process characterized by a phenotypic change of VSMCs to osteoblast-like cells with increased bone matrix protein expression, and that hyperglycaemia may directly induce these changes.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Calcinosis; Cattle; Cells, Cultured; Core Binding Factor Alpha 1 Subunit; Diabetic Angiopathies; Glucose; Humans; Muscle, Smooth, Vascular; Transforming Growth Factor beta; Vascular Diseases

Chronic renal failure is complicated by high cardiovascular mortality. One key contributor to this mortality is vascular calcification, for which no therapy currently exists. Bone morphogenetic protein 7 is an essential renal morphogen that maintains renal tubular differentiation in the adult and is downregulated in renal failure. Several studies have demonstrated its efficacy in treating various renal diseases in rodents, and it was hypothesized that it would also be an effective treatment of vascular calcification in this setting. Uremia was imposed on LDL receptor null mice (a model of atherosclerosis), which were then treated with bone morphogenetic protein 7 for 15 wk. Uremic animals had increased vascular calcification by histology and chemical analysis. Calcification in treated animals was similar to or less than non-uremic control animals. Cells exhibiting an osteoblast-like phenotype in the vessel wall may be important in the etiology of vascular calcification. Expression of osteocalcin was assessed as a marker of osteoblastic function, and it is shown that it is increased in untreated uremic animals but downregulated to levels similar to non-uremic control animals with treatment. The data are compatible with bone morphogenetic protein 7 deficiency as a pathophysiologic factor in chronic renal failure, and they demonstrate its efficacy as a potential treatment of vascular calcification.

Topics: Animals; Arteriosclerosis; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcinosis; Immunohistochemistry; Kidney Failure, Chronic; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteocalcin; Receptors, LDL; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Vascular Diseases

Plasminogen activator inhibitor type 1 (PAI-1) is the primary physiologic inhibitor of plasminogen activator in vivo. Increased PAI-1 expression is associated with arteriosclerosis. Transforming growth factor-beta (TGF-beta) induces PAI-1 production via Smads.. In vivo, TGF-beta receptors (TbetaRs), Smad2, Smad3, and Smad4, PAI-1, and Smad2 phosphorylation were examined by immunohistochemistry in 3 native aortas, 14 rat aortic syngrafts, and 19 allografts collected at 15, 30, and 45 days post-transplantation. In vitro, phosphorylation of Smad2 and induction of PAI-1 mRNA in human aortic smooth muscle cells (SMCs) in response to TGF-beta treatment were detected by Western blot and by TaqMan real-time RT-PCR, respectively.. Immunohistochemical staining revealed that vascular parenchymal cells contained TbetaRI, TbetaRII, Smad2, Smad3, and Smad4, known signaling transducers for TGF-beta/Smad pathway, in all samples. Intense staining for phospho-Smad2 was observed in 94% of endothelial cells (ECs), 86% of intimal cells, 27% of medial SMCs, and 38% of adventitial cells at all 3 time points in all aortic allografts, but only in 5% of ECs in syngrafts. PAI-1 immunoreactivity was detected in similar number of cells, and from consecutive sections, phospho-Smad2 colocalized with PAI-1, in the aortic allografts. Low basal level PAI-1 expression was observed in aortic syngrafts and native vessels. Smad2 phosphorylation and time-dependent PAI-1 induction were detected in cultured SMCs upon TGF-beta treatment.. Phospho-Smad2 staining in aortic allografts indicates the activation of TGF-beta signaling in allo-transplantation; and co-localization of PAI-1 and phospho-Smad2 suggests that PAI-1 upregulation is mediated mainly by TGF-beta/Smad pathway in aortic allografts.

Topics: Animals; Aorta; DNA-Binding Proteins; Graft Survival; Heart Transplantation; Humans; Immunohistochemistry; In Vitro Techniques; Male; Myocardium; Plasminogen Activator Inhibitor 1; Rats; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Smad Proteins; Smad2 Protein; Smad3 Protein; Smad4 Protein; Trans-Activators; Transforming Growth Factor beta; Up-Regulation; Vascular Diseases

Topics: Animals; DNA-Binding Proteins; Gene Expression Regulation; Humans; Muscle Proteins; Muscle, Smooth, Vascular; Nuclear Proteins; Repressor Proteins; Signal Transduction; Smad6 Protein; Trans-Activators; Transforming Growth Factor beta; Vascular Diseases

to compare patients with abdominal aortic aneurysm (AAA) and aortic occlusive disease (AOD) with regard to risk factors for atherosclerosis, co-morbid conditions and inflammatory activity.. a total of 155 patients undergoing abdominal aortic surgery between January 1993 and October 1997: 82 (53%) had aneurysmal disease and 73 (47%) had occlusive disease. Principal risk factors were compared: age; gender; smoking; hypertension; hyperlipidaemia; diabetes mellitus; severe peripheral vascular disease (PVD) and ischaemic heart disease. Aortic wall tissue samples were obtained during surgery. A prospective blind analysis was performed for the presence of inflammatory cytokines TNF-alpha, IL-1 beta, IL-6 and TGF-beta.. the average age of AAA patients was 74 years (50-88), while that of AOD patients was 61 years (43-82) (p<0.0001). Diabetes mellitus was found to be much more prevalent in the AOD group (p<0.001), while hypertension and severe PVD were more prevalent in the AAA group (p<0.001). No differences were found concerning any of the risk factors. Inflammatory cytokine activity: AAA tissue samples contained significantly higher mean TNF-alpha and IL-6 levels compared to the AOD samples (5.6+/-2.7 x 10 E-4 vs. 4.4+/-2.7 x 10 E-5 atmoles/microl (p=0. 01), and 0.6+/-0.4 vs. 0.01+/-0.006 atmoles/microl (p=0.02) respectively). No differences were found related to IL-1 beta and TGF-beta.. (1) Patients with AAA have fewer atherosclerotic risk factors than do patients with AOD. (2) Patients with AAA and AOD have significantly different inflammatory activity. (3) The data supports the hypothesis that AAA and AOD are probably two different pathological entities.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Aortic Diseases; Coronary Disease; Diabetes Complications; Female; Humans; Hyperlipidemias; Hypertension; Interleukin-1; Interleukin-6; Male; Middle Aged; Polymerase Chain Reaction; Prospective Studies; Risk Factors; Sex Factors; Smoking; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Diseases

The purpose of this study was to assess the role of transforming growth factor (TGF)-beta1 in the development of diabetes-associated mesenteric vascular hypertrophy and in the antitrophic effect of angiotensin converting enzyme inhibitors.. Streptozotocin-induced diabetic and control Sprague-Dawley rats were randomly allocated to treatment with the angiotensin converting enzyme inhibitor ramipril or to no treatment and were killed 1 or 3 weeks after the streptozotocin injection. Blood was collected and mesenteric vessels removed. Mesenteric vascular weight was measured and TGF-beta1 and alpha1 (type IV) collagen messenger (m)RNA levels were analysed by Northern analysis. Immunohistochemical analyses for TGF-beta1 and type IV collagen were also performed.. The diabetic rats had increased mesenteric vessel weight at 3 weeks but not at 1 week and a concomitant rise in mesenteric TGF-beta1 and in alpha1 (type IV) collagen mRNA levels. Ramipril treatment attenuated mesenteric vessel hypertrophy and prevented the increase in TGF-beta1 and alpha1 (type IV) collagen mRNA levels after 3 weeks of diabetes. The immunohistochemical analysis revealed that diabetes was associated with increased TGF-beta1 and type IV collagen protein and extracellular matrix accumulation in mesenteric vessels, and this increase was reduced by ramipril treatment.. These results support the concept that TGF-beta is involved in the changes associated with diabetic vascular disease, and suggest a mechanism by which angiotensin converting enzyme inhibitors exert their antitrophic effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Blood Pressure; Blotting, Northern; Body Weight; Collagen; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Gene Expression; Immunohistochemistry; Male; Ramipril; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta; Vascular Diseases

The binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) on cell surfaces has the potential to influence degradation of extracellular matrix (ECM). Thus, uPA bound to monocyte/macrophages and its interactions with plasminogen activator inhibitors types 1 and 2 (PAI-1 and PAI-2) may modify atherogenesis by altering cell-associated proteolytic activity, degradation of ECM, and neointimal formation at sites of vascular injury.. To determine whether the expression of proteins on the surface of cells involved in fibrinolysis changes in human cells in response to mediators implicated in atherogenesis, we exposed U937 cells (an immortal human monocyte-like cell line) to transforming growth factor-beta (TGF-beta) and to thrombin. Induction of uPAR mRNA occurred with TGF-beta (5 ng/mL) in a time-dependent fashion (P = .05; n = 4). Thrombin (5 National Institutes of Health [NIH] U/mL) increased uPAR mRNA by 2.8-fold above control (n = 4) without altering PAI-1 mRNA or protein synthesis (n = 4). The increase in uPAR gene expression in cells exposed to either TGF-beta or thrombin translated into a functional increase in cell-surface proteolytic activity. Under control conditions, U937 cells expressed PAI-2 but not PAI-1 mRNA. PAI-2 mRNA expression increased (P < .05; n = 4) with thrombin (5 NIH U/mL) but was suppressed by TGF-beta (5 ng/mL). TGF-beta induced PAI-1 mRNA within 6 hours accompanied by a 9-fold increase in PAI-1 protein from 6 hours (2.9 +/- 1.9 ng/mL) to 24 hours (20.0 +/- 9.6 ng/mL, P = .005; n = 3) paralleled by increased synthesis as shown in metabolic labeling experiments with 35S-methionine and immunoprecipitation of labeled PAI-1. PAI-1 mRNA and protein expression were seen in human coronary artery atherectomy specimens as well and were localized to analogous monocyte/macrophages and to smooth muscle cells as judged from results of in situ hybridization and immunocytochemistry studies.. The results indicate that there is induction of PAI-1 and uPAR in U937 cells exposed to TGF-beta and thrombin. In atheroma, analogous processes may modulate early migration of luminal monocytes into the subintimal space and proteolysis of ECM. Thus, cell surface, monocyte-directed fibrinolysis may influence atherosclerosis, restenosis, or both.

Topics: Cell Line; Humans; Immunohistochemistry; In Situ Hybridization; Macrophages; Monocytes; Plasminogen; Plasminogen Activator Inhibitor 1; Plasminogen Activator Inhibitor 2; Plasminogen Activators; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; RNA, Messenger; Thrombin; Transforming Growth Factor beta; Urokinase-Type Plasminogen Activator; Vascular Diseases

Human atheromata obtained in vivo were used to test the hypothesis that transforming growth factor-beta 1 plays a role in the development of vascular restenosis. We analyzed 28 specimens from patients with primary atherosclerotic or restenotic lesions; 26 of these were obtained by directional atherectomy and 2 at the time of coronary bypass surgery. Seven control tissues included operatively excised segments of human internal mammary artery, myocardium, and unused portions of vein graft obtained intraoperatively. From these 35 specimens, 210 sections were examined using in situ hybridization. Measurement of silver grains/nucleus disclosed that expression of transforming growth factor-beta 1 mRNA was highest in restenotic tissues (P < 0.001 vs. primary atherosclerotic tissues) and lowest in nonatherosclerotic (control) tissues. In cultures of human vascular smooth muscle cells grown from explants of internal mammary artery, expression of mRNA for transforming growth factor-beta 1 was significantly greater in subconfluent than in confluent smooth muscle cells (P = 0.05). Transforming growth factor type-beta III receptor was expressed in cell cultures and undetectable in the tissue specimens. Sections taken adjacent to those studied by in situ hybridization were examined by immunohistochemistry using antibodies against transforming growth factor-beta 1 and alpha-actin (as a marker for smooth muscle cells) and disclosed transforming growth factor-beta 1 in smooth muscle cells present in these sections. These findings are consistent with the concept that transforming growth factor-beta 1 plays an important role in modulating repair of vascular injury, including restenosis, after balloon angioplasty.

Topics: Actins; Arteriosclerosis; Humans; Immunohistochemistry; In Situ Hybridization; Platelet-Derived Growth Factor; Receptors, Cell Surface; Receptors, Transforming Growth Factor beta; Recurrence; RNA, Messenger; Transforming Growth Factor beta; Vascular Diseases