transforming-growth-factor-beta and Cerebrovascular-Disorders

Transforming growth factor betas (TGF-βs) belong to three isoforms (TGF-β1, TGF-β2 and TGF-β3) members of a large pleiotropic superfamily of around 100 distinct proteins participating in the regulation of key events of development and disease, and tissue repair. In the central nervous system (CNS), all the three isoforms are produced by both glial and neuronal cells and are involved in essential tissue functions such as cell-cycle control, regulation of early development and differentiation, neuronal survival and astrocytes differentiation. Recent findings have shown abnormally increase of the levels of TGF-β1 in the brain of patients suffering Alzheimer's disease (AD), an elderly pathology reaching individuals over 65-years-old which present well-known hallmarks, including cerebrovascular deficiency, abnormal deposition of amyloid beta (Aβ), cholinergic denervation, neuroinflammation, neurofibrillary tangles and progressive loss of memory. However, related to the pathological features of AD, the brain overexpression of TGF-β1 was associated with neuroinflammation, accumulation of extracellular matrix compounds and cerebrovascular stiffness, neuronal apoptosis along with the development of vascular hypertrophy. Consistent with these observations, transgenic mice model (TGF mice) overexpressing constitutively TGF-β1 fully mimicked AD-like cerebrovascular pathology. Taken altogether, these data suggest the involvement of TGF-β1in the pathogenesis of AD, particularly in the cerebrovascular pathology which is of interest in the present review that will discuss the contribution of TGF-β1 in the cerebrovascular physiopathology of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebrovascular Disorders; Humans; Mice; Mice, Transgenic; Transforming Growth Factor beta; Transforming Growth Factor beta1

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a life-threatening, inherited, nonhypertensive arteriole disease of the brain. Therapeutic strategy for CARASIL is limited because its pathogenesis is not clear. We previously reported the first family with CARASIL in China, which involves a high-temperature requirement serine protease gene mutation (HtrA1. Food maze and water maze experiments were used in the behavioral studies. Pathological studies were carried out by arteriole labeling staining and electron microscopy. The mRNA and protein expression levels of the key factors of TGF-β/Smad signaling pathway (TGF-β, Smad2, Smad3, and Smad4) in the brain of the model mice were detected by immunohistochemistry, real-time quantitative polymerase chain reaction (RT-PCR), and Western blot assay.. The food maze and water maze experiment data showed significant differences between the Mut and wild-type (WT) mice in the first time to find food, the time to contact the escape table for the first time, and the number of times to travel in the escape table quadrant (p < 0.001). The results of vascular labeling staining showed that some small arteries in the brain of Mut mice lost normal structure. The results of electron microscopy showed that the cell morphologies in the cortex and hippocampus of Mut mice were abnormal; the number of synapses was reduced; the walls of capillaries, venules, and arterioles thickened; lumen stenosis and other abnormal phenomenon occurred; and lipofuscin deposition and autophagosomes were found in the hippocampus. Immunohistochemistry, RT-PCR, and Western Blot results showed that the mRNA and protein expression levels of TGF-β, Smad2, and Smad3 in the brain of Mut mice increased to different degrees.. The most significant innovation of this study is the first study on the pathogenesis of CARASIL disease using model animals. The Mut mice can well simulate the pathogenesis of CARASIL in behavioral and pathological aspects. The TGF-β/Smad signaling pathway, which is involved in the pathogenesis of CARASIL, is abnormally upregulated in the brain of Mut mice.

Topics: Alopecia; Animals; Cerebral Arterial Diseases; Cerebral Infarction; Cerebrovascular Disorders; Cognitive Dysfunction; High-Temperature Requirement A Serine Peptidase 1; Leukoencephalopathies; Mice; RNA, Messenger; Signal Transduction; Spinal Diseases; Transforming Growth Factor beta

The purpose of this study was to investigate the significance of circulating micro RNAs (miRNAs) in the pathogenesis of reversible cerebral vasoconstriction syndrome (RCVS).. We prospectively recruited 3 independent cohorts of patients with RCVS and age-matched and sex-matched controls in a single medical center. Next-generation small RNA sequencing followed by quantitative polymerase chain reaction (PCR) was used to identify and validate differentially expressed miRNAs, which was cross-validated in migraine patients in ictal stage or interictal stage. Computational analysis was used to predict the target genes of miRNAs, followed by in vitro functional analysis.. We identified a panel of miRNAs including miR-130a-3p, miR-130b-3p, let-7a-5p, let-7b-5p, and let-7f-5p that well differentiated patients with RCVS from controls (area under the receiver operating characteristics curve [AUC] was 0.906, 0.890, and 0.867 in the 3 cohorts, respectively). The abundance of let-7a-5p, let-7b-5p, and let-7f-5p, but not miR-130a-3p nor miR-130b-3p, was significantly higher in patients with ictal migraine compared with that of controls and patients with interictal migraine. Target prediction and pathway enrichment analysis suggested that the transforming growth factor-β signaling pathway and endothelin-1 responsible for vasomotor control might link these miRNAs to RCVS pathogenesis, which was confirmed in vitro by transfecting miRNAs mimics or incubating the patients' cerebrospinal fluid (CSF) in 3 different vascular endothelial cells. Moreover, miR-130a-3p was associated with imaging-proven disruption of the blood-brain barrier (BBB) in patients with RCVS and its overexpression led to reduced transendothelial electrical resistance (ie, increased permeability) in in vitro human BBB model.. We identified the circulating miRNA signatures associated with RCVS, which may be functionally linked to its headache, BBB integrity, and vasomotor function. ANN NEUROL 2021;89:459-473.

Topics: Adult; Blood-Brain Barrier; Capillary Permeability; Case-Control Studies; Cerebrovascular Disorders; Circulating MicroRNA; Computer Simulation; Electric Impedance; Endothelial Cells; Endothelin-1; Female; High-Throughput Nucleotide Sequencing; Human Umbilical Vein Endothelial Cells; Humans; In Vitro Techniques; Male; MicroRNAs; Middle Aged; Migraine Disorders; Reproducibility of Results; Sequence Analysis, RNA; Transforming Growth Factor beta; Vasoconstriction; Vasomotor System

High temperature requirement A1 (HTRA1) is a serine protease playing a modulatory role in various cell processes, particularly in the regulation of transforming growth factor-β (TGF-β) signaling. A deleterious role in late-onset cerebral small vessel diseases (CSVDs) of heterozygous HTRA1 mutations, otherwise causative in homozygosity of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, was recently suggested. However, the pathomechanism of these heterozygous mutations is still undefined. Our aim is to evaluate the expression profile and activity of HTRA1 on TGF-β signaling in fibroblasts from four subjects carrying the HTRA1 heterozygous mutations-p.E42Dfs*173, p.A321T, p.G295R, and p.Q151K. We found a 50% reduction of HTRA1 expression in HTRA1 mutation carriers compared to the control. Moreover, we showed no changes in TGF-β signaling pathway downstream intermediate, Phospho Smad2/3. However, we found overexpression of genes involved in the extracellular matrix formation in two heterozygous HTRA1 carriers. Our results suggest that each heterozygous HTRA1 missense mutation displays a different and peculiar HTRA1 expression pattern and that CSVD phenotype may also result from 50% of HTRA1 expression.

Topics: Alopecia; Cells, Cultured; Cerebral Infarction; Cerebrovascular Disorders; Female; Fibroblasts; Heterozygote; High-Temperature Requirement A Serine Peptidase 1; Humans; Leukoencephalopathies; Male; Middle Aged; Mutation; Signal Transduction; Spinal Diseases; Transcriptome; Transforming Growth Factor beta

Transforming growth factor β (TGF-β) serves critical functions in brain injury, especially in cerebral ischemia; however, apart from its neuroprotective effects, its role in regulating neurogenesis is unclear. TGF-β acts in different ways; the most important, canonical TGF-β activity involves TGF-β receptor I (TβRI) or the activin receptor-like kinase 5 (ALK5) signaling pathway. ALK5 signaling is a major determinant of adult neurogenesis. In our previous studies, growth arrest and DNA damage protein 45b (Gadd45b) mediated axonal plasticity after stroke. Here, we hypothesized that ALK5 signaling regulates neural plasticity and neurological function recovery after cerebral ischemia/reperfusion (I/R) via Gadd45b. First, ALK5 expression was significantly increased in middle cerebral artery occlusion/reperfusion (MCAO/R) rats. Then, we knocked down or overexpressed ALK5 with lentivirus (LV) in vivo. ALK5 knockdown reduced axonal and dendritic plasticity, with a concomitant decrease in neurological function recovery. Conversely, ALK5 overexpression significantly increased neurogenesis as well as functional recovery. Furthermore, ALK5 mediated Gadd45b protein levels by regulating Smad2/3 phosphorylation. Finally, ALK5 coimmunoprecipitated with Gadd45b. Our results suggested that the ALK5 signaling pathway plays a critical role in mediating neural plasticity and neurological function recovery via Gadd45b after cerebral ischemia, representing a new potential target for cerebral I/R injury.

Topics: Animals; Antigens, Differentiation; Brain; Cerebrovascular Disorders; Disease Models, Animal; Gene Expression Regulation; Male; Middle Cerebral Artery; Neurogenesis; Neuronal Plasticity; Neurons; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptor, Transforming Growth Factor-beta Type I; Recovery of Function; Reperfusion Injury; RNA, Small Interfering; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta

Marfan syndrome (MFS) is a connective tissue disorder that is often associated with the fibrillin-1 (Fbn1) gene mutation and characterized by cardiovascular alterations, predominantly ascending aortic aneurysms. Although neurovascular complications are uncommon in MFS, the improvement in Marfan patients' life expectancy is revealing other secondary alterations, potentially including neurovascular disorders. However, little is known about small-vessel pathophysiology in MFS. MFS is associated with hyperactivated transforming growth factor (TGF)-β signaling, which among numerous other downstream effectors, induces the NADPH oxidase 4 (Nox4) isoform of NADPH oxidase, a strong enzymatic source of H2O2 We hypothesized that MFS induces middle cerebral artery (MCA) alterations and that Nox4 contributes to them. MCA properties from 3-, 6-, or 9-mo-old Marfan (Fbn1(C1039G/+)) mice were compared with those from age/sex-matched wild-type littermates. At 6 mo, Marfan compared with wild-type mice developed higher MCA wall/lumen (wild-type: 0.081 ± 0.004; Marfan: 0.093 ± 0.002; 60 mmHg; P < 0.05), coupled with increased reactive oxygen species production, TGF-β, and Nox4 expression. However, wall stiffness and myogenic autoregulation did not change. To investigate the influence of Nox4 on cerebrovascular properties, we generated Marfan mice with Nox4 deficiency (Nox4(-/-)). Strikingly, Nox4 deletion in Marfan mice aggravated MCA wall thickening (cross-sectional area; Marfan: 6,660 ± 363 μm(2); Marfan Nox4(-/-): 8,795 ± 824 μm(2); 60 mmHg; P < 0.05), accompanied by decreased TGF-β expression and increased collagen deposition and Nox1 expression. These findings provide the first evidence that Nox4 mitigates cerebral artery structural changes in a murine model of MFS.

Topics: Animals; Arterial Pressure; Cerebrovascular Disorders; Collagen; Disease Models, Animal; Disease Progression; Female; Fibrillin-1; Genetic Predisposition to Disease; Male; Marfan Syndrome; Mechanotransduction, Cellular; Mice, Knockout; Middle Cerebral Artery; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; NADPH Oxidase 4; NADPH Oxidases; Phenotype; Reactive Oxygen Species; Stress, Mechanical; Time Factors; Transforming Growth Factor beta; Vascular Remodeling; Vascular Stiffness

The objective of this study was to evaluate the systemic and cerebral effects of different postoperative hematocrit management following cardiopulmonary bypass and deep hypothermic circulatory arrest.. Animal case study.. Laboratory.. Four-week-old Yorkshire piglets.. Twelve piglets were subjected to cardiopulmonary bypass (hematocrit = 25%) and 100 mins of deep hypothermic circulatory arrest (15 degrees C). After weaning cardiopulmonary bypass, they were randomized to either group L or H, in which the postoperative hematocrit was maintained approximately 20% vs. approximately 30%, respectively, and survived for 6 hrs.. Changes in body weight, bioimpedance, and colloid oncotic pressure were assessed. Near-infrared spectroscopy and immunohistochemical assays for cerebral transforming growth factor-beta(1) and caspase-3 were performed. Postoperative weight gain (kg) and decreases in bioimpedance (ohms) were significantly less in group H (1.5 +/- 0.2 [H] vs. 2.4 +/- 0.6 [L], p = .01; 39.3 +/- 15.5 [H] vs. 89.1 +/- 29.6 [L], p = .01). Mean colloid oncotic pressure (mm Hg) was significantly higher in group H (10.8 +/- 1.6 [H] vs. 8.2 +/- 0.8 [L], p = .01) at 6 hrs postoperatively. Oxyhemoglobin, oxidized cytochrome aa(3) (muM x differential path-length factor), and tissue oxygenation index (%) were significantly better in group H (65.7 +/- 31.8 [H] vs. -104.7 +/- 55.2 [L], p = .0001; 0.52 +/- 4.1 [H] vs. -12.8 +/- 6.1 [L], p = .0001, and 55.7 +/- 4.6% [H] vs. 45.3 +/- 6.4% [L], p = .004, respectively). Cerebral transforming growth factor-beta(1) and caspase-3 scores were significantly better in group H (3.0 +/- 0.6 [H] vs. 1.9 +/- 0.9 [L], p = .04 and 1.8 +/- 0.5 [H] vs. 3.2 +/- 0.8 [L], p = .02, respectively). Mean arterial pressure (mm Hg) was consistently higher with group H (94.7 +/- 13.0 [H] vs. 78.3 +/- 11.5 [L], p = .003) despite comparable central venous pressure ( approximately 11 mm Hg).. Lower postoperative hematocrit was associated with increased fluid retention, lower perfusion pressure, and worse cerebrovascular injury following deep hypothermic circulatory arrest. Postoperative hematocrit management may have profound systemic and cerebral effects after deep hypothermic circulatory arrest and merits further investigation.

Topics: Animals; Body Water; Body Weight; Cardiopulmonary Bypass; Caspase 3; Caspases; Cerebral Cortex; Cerebrovascular Disorders; Electric Impedance; Hematocrit; Hemoglobins; Hypothermia, Induced; Oxygen Consumption; Oxyhemoglobins; Postoperative Period; Swine; Transforming Growth Factor beta; Transforming Growth Factor beta1

Immune mechanisms contribute to cerebral ischemic injury. Therapeutic immunosuppressive options are limited due to systemic side effects. We attempted to achieve immunosuppression in the brain through oral tolerance to myelin basic protein (MBP). Lewis rats were fed low-dose bovine MBP or ovalbumin (1 mg, five times) before 3 h of middle cerebral artery occlusion (MCAO). A third group of animals was sensitized to MBP but did not survive the post-stroke period. Infarct size at 24 and 96 h after ischemia was significantly less in tolerized animals. Tolerance to MBP was confirmed in vivo by a decrease in delayed-type hypersensitivity to MBP. Systemic immune responses, characterized in vitro by spleen cell proliferation to Con A, lipopolysaccharide, and MBP, again confirmed antigen-specific immunologic tolerance. Immunohistochemistry revealed transforming growth factor beta1 production by T cells in the brains of tolerized but not control animals. Systemic transforming growth factor beta1 levels were equivalent in both groups. Corticosterone levels 24 h after surgery were elevated in all sham-operated animals and ischemic control animals but not in ischemic tolerized animals. These results demonstrate that antigen-specific modulation of the immune response decreases infarct size after focal cerebral ischemia and that sensitization to the same antigen may actually worsen outcome.

Topics: Animals; Cerebrovascular Disorders; Corticosterone; Hypersensitivity, Delayed; Immune Tolerance; Immunohistochemistry; Ischemic Attack, Transient; Male; Myelin Basic Protein; Rats; Rats, Inbred Lew; Transforming Growth Factor beta

Our previous study in vivo suggested that vascular smooth muscle cells (VSMCs) in stroke-prone spontaneously hypertensive rats (SHRSP) were vulnerable when plasma components were deficient. Therefore, we cultured VSMCs isolated from normotensive and hypertensive rats to clarify the weakness of VSMCs isolated from hypertensive rats and maintained in plasma-deficient conditions by employing ultrastructural and biochemical analyses. VSMCs, obtained from normotensive rats and cultured without fetal bovine serum (FBS) for 1 week, were intact and well differentiated; without FBS for 2 weeks retained their original structures except for several degenerative changes. VSMCs, obtained from hypertensive rats and cultured without FBS for 2 weeks, were extensively damaged and lost their cell organelles. Apoptotic bodies were frequently observed. We also cultured VSMCs in medium containing a variety of growth factors. VSMCs obtained from normotensive rats and cultured with epidermal growth factor or insulin-like growth factor-1 for 2 weeks were almost intact, as were VSMCs from hypertensive rats, although some degenerative changes of cell organelles were observed. VSMCs from hypertensive rats, maintained with platelet-derived growth factor-BB or basic fibroblast growth factor, were generally in poor condition. Thus VSMCs from hypertensive rats have hereditary weaknesses in cell survival including apoptosis and require specific growth factors for their maintenance.

Topics: Animals; Cattle; Cerebrovascular Disorders; Fibroblast Growth Factors; Growth Substances; Hypertension; L-Lactate Dehydrogenase; Muscle, Smooth, Vascular; Platelet-Derived Growth Factor; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Somatomedins; Transforming Growth Factor beta

Cytokine changes in patients with acute stroke have been insufficiently studied. The purpose of this study was to delineate the characteristics of serial changes of serum interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) in patients with cerebral infarction and intracerebral hemorrhage.. We serially (within 24 hours, at day 3, and at day 7) measured the serum levels of IL-6 and TGF-beta in 29 patients with acute stroke (10 with large cortical cerebral infarction, 9 with subcortical small infarction, and 10 with intracerebral hemorrhage). As an index of brain damage. S-100 protein was also measured. Twelve age-matched healthy subjects were tested as a control.. S-100 protein was detected in only 11 patients with large infarction or intracerebral hemorrhage. Its level peaked at day 3 in patients with infarction, whereas it peaked within 24 hours in those with intracerebral hemorrhage. The level of IL-6 was most markedly elevated at day 1, which tended to decrease thereafter. However, its level remained significantly elevated compared with that of the control group even at day 7. The level of TGF-beta was significantly decreased at day 1 and day 3 and tended to return toward the control value thereafter. The levels of both cytokines were not significantly different among the three different stroke subtypes and were not correlated with the number of blood leukocytes and platelets.. The alteration of IL-6 and TGF-beta levels, which occurs rapidly after acute stroke regardless of the subtype, may reflect the changing immunological-inflammatory status of these patients and does not appear to reflect merely the consequence of the brain damage.

Topics: Acute Disease; Aged; Aged, 80 and over; Cerebrovascular Disorders; Female; Humans; Interleukin-6; Male; Middle Aged; S100 Proteins; Transforming Growth Factor beta

1. We investigated the protective effects of an angiotensin-converting enzyme inhibitor (ACEI) and a Ca antagonist on vascular injury in hypertension. 2. Thirteen week old stroke-prone spontaneously hypertensive rats (SHRSP) were orally given cilazapril (ACEI 10 mg per kg day) or nifedipine (Ca antagonist 30 mg kg per day) for 12 weeks. After the treatment, the aorta and superior mesenteric artery were excised, and subjected to the extraction of RNA. mRNA levels for the transforming growth factor-beta1 (TGF-beta1) and extracellular matrix components such as fibronectin (FN), collagen type I (CoI), type III (CoIII) and type IV (CoIV) and laminin, were measured by northern blot analysis, using each specific cDNA probe. 3. In the mesenteric artery of SHRSP, TGF-beta1 mRNA levels were increased compared with Wistar-Kyoto (WKY) rats, being accompanied by a significant increase in mRNA levels for FN, CoI, CoIII, CoIV and laminin. In the aorta, only TGF-beta1 and fibronectin mRNAs were increased in SHRSP, but collagen and laminin were not increased. 4. Both cilazapril and nifedipine, to similar extents, suppressed the above mentioned increased gene expressions in both mesenteric artery and aorta, being associated with the improvement of vascular hypertrophy. 5. These results suggest that TGF-beta1 may be responsible for smooth muscle cell hypertrophy and the increased deposition of extracellular matrix in hypertensive blood vessels. Both cilazapril and nifedipine may lessen hypertensive vascular thickening, by suppressing the gene expression of TGF-beta1 and extracellular matrix.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autoradiography; Blood Vessels; Blotting, Northern; Calcium Channel Blockers; Cerebrovascular Disorders; Cilazapril; Extracellular Matrix; Gene Expression; Male; Nifedipine; Rats; Rats, Inbred SHR; RNA, Messenger; Transforming Growth Factor beta

We examined the effects of TCV-116, a non-peptide selective AT1 receptor antagonist, on cellular phenotype and on the expression of the transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix genes in the kidneys of stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were given vehicle or TCV-116 (10 mg/kg/day) by gastric gavage for 10 weeks (from the age of 22 to 32 weeks). Renal mRNA levels were measured by Northern blot analysis. In vehicle-treated 32-week-old SHRSP, urinary albumin excretion per 24 h was about 26-fold greater than that in age-matched Wistar-Kyoto (WKY) rats, and the mRNA levels of renal TGF-beta 1, fibronectin and collagen types I and III in SHRSP were all several-fold higher than those in WKY. Immunohistochemical studies showed the prominent presence of alpha-smooth muscle actin-expressing glomerular cells in SHRSP, in contrast to their absence in WKY. Treatment of SHRSP with TCV-116 decreased urinary albumin excretion and renal mRNA levels for TGF-beta 1 and for the above-mentioned extracellular matrix components. TCV-116 prevented the phenotypic modulation of glomerular cells in SHRSP. These results suggest that AT1 receptor antagonists may have powerful renal protective effects.

Topics: Albuminuria; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Cerebrovascular Disorders; Extracellular Matrix; Gene Expression; Hypertension, Renal; Kidney; Kidney Glomerulus; Male; Phenotype; Prodrugs; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; RNA, Messenger; Sclerosis; Tetrazoles; Transforming Growth Factor beta

Topics: Animals; Aorta; Cerebrovascular Disorders; Disease Susceptibility; Hypertension; In Vitro Techniques; Male; Mink; Potassium; Rats; Rats, Inbred SHR; Transforming Growth Factor beta