elastin and Constriction--Pathologic

Elastin is a long-lived extracellular matrix protein that is organized into elastic fibers that provide elasticity to the arterial wall, allowing stretch and recoil with each cardiac cycle. By forming lamellar units with smooth muscle cells, elastic fibers transduce tissue-level mechanics to cell-level changes through mechanobiological signaling. Altered amounts or assembly of elastic fibers leads to changes in arterial structure and mechanical behavior that compromise cardiovascular function. In particular, genetic mutations in the elastin gene (

Topics: Animals; Aorta; Arteries; Constriction, Pathologic; Elastin; Mice; Myocytes, Smooth Muscle

The underlying cause of congenital supravalvular aortic stenosis (SVAS) has recently been identified as a loss-of function mutation of the elastin gene on chromosome 7q11.23, resulting in an obstructive arteriopathy of varying severity, which is most prominent at the aortic sinutubular junction. The generalized nature of the disease explains the frequent association with stenoses of systemic and pulmonary arteries. Furthermore, localization of the supravalvular stenosis at the level of the commissures of the aortic valve has important implications for both aortic valve function and coronary circulation. This review summarizes the recent advances with regard to the pathogenesis of SVAS and describes the multitude of clinically relevant pathologic features other that the mere 'supra-aortic' narrowing that have important implications for surgical therapy.

Topics: Aorta; Aortic Stenosis, Supravalvular; Constriction, Pathologic; Coronary Circulation; Elastin; Humans; Pulmonary Artery; Williams Syndrome

Obstructive arterial diseases, including supravalvular aortic stenosis (SVAS), atherosclerosis, and restenosis, share 2 important features: an abnormal or disrupted elastic lamellae structure and excessive smooth muscle cells (SMCs). However, the relationship between these pathological features is poorly delineated. SVAS is caused by heterozygous loss-of-function, hypomorphic, or deletion mutations in the elastin gene (ELN), and SVAS patients and elastin-mutant mice display increased arterial wall cellularity and luminal obstructions. Pharmacological treatments for SVAS are lacking, as the underlying pathobiology is inadequately defined. Herein, using human aortic vascular cells, mouse models, and aortic samples and SMCs derived from induced pluripotent stem cells of ELN-deficient patients, we demonstrated that elastin insufficiency induced epigenetic changes, upregulating the NOTCH pathway in SMCs. Specifically, reduced elastin increased levels of γ-secretase, activated NOTCH3 intracellular domain, and downstream genes. Notch3 deletion or pharmacological inhibition of γ-secretase attenuated aortic hypermuscularization and stenosis in Eln-/- mutants. Eln-/- mice expressed higher levels of NOTCH ligand JAGGED1 (JAG1) in aortic SMCs and endothelial cells (ECs). Finally, Jag1 deletion in SMCs, but not ECs, mitigated the hypermuscular and stenotic phenotype in the aorta of Eln-/- mice. Our findings reveal that NOTCH3 pathway upregulation induced pathological aortic SMC accumulation during elastin insufficiency and provide potential therapeutic targets for SVAS.

Topics: Amyloid Precursor Protein Secretases; Animals; Aorta; Aortic Stenosis, Supravalvular; Constriction, Pathologic; Elastin; Endothelial Cells; Humans; Jagged-1 Protein; Mice; Receptor, Notch3

Topics: Constriction, Pathologic; Coronary Stenosis; Elastin; Humans; Williams Syndrome

Topics: Adult; Arteries; Constriction, Pathologic; Elastin; Female; Humans; Magnetic Resonance Angiography; Williams Syndrome

Elastin gene deletion or mutation leads to arterial stenoses due to vascular smooth muscle cell (SMC) proliferation. Human induced pluripotent stem cells-derived SMCs can model the elastin insufficiency phenotype in vitro but show only partial rescue with rapamycin. Our objective was to identify drug candidates with superior efficacy in rescuing the SMC phenotype in elastin insufficiency patients. Approach and Results: SMCs generated from induced pluripotent stem cells from 5 elastin insufficiency patients with severe recurrent vascular stenoses (3 Williams syndrome and 2 elastin mutations) were phenotypically immature, hyperproliferative, poorly responsive to endothelin, and exerted reduced tension in 3-dimensional smooth muscle biowires. Elastin mRNA and protein were reduced in SMCs from patients compared to healthy control SMCs. Fourteen drug candidates were tested on patient SMCs. Of the mammalian target of rapamycin inhibitors studied, everolimus restored differentiation, rescued proliferation, and improved endothelin-induced calcium flux in all patient SMCs except one Williams syndrome. Of the calcium channel blockers, verapamil increased SMC differentiation and reduced proliferation in Williams syndrome patient cells but not in elastin mutation patients and had no effect on endothelin response. Combination treatment with everolimus and verapamil was not superior to everolimus alone. Other drug candidates had limited efficacy.. Everolimus caused the most consistent improvement in SMC differentiation, proliferation and in SMC function in patients with both syndromic and nonsyndromic elastin insufficiency, and offers the best candidate for drug repurposing for treatment of elastin insufficiency associated vasculopathy.

Topics: Arterial Occlusive Diseases; Case-Control Studies; Cell Differentiation; Cell Line; Cell Proliferation; Constriction, Pathologic; Elastin; Everolimus; Female; Heterozygote; Humans; Induced Pluripotent Stem Cells; Infant; Male; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Phenotype; Protein Kinase Inhibitors; TOR Serine-Threonine Kinases; Williams Syndrome

Supravalvular aortic stenosis (SVAS) is a narrowing of the aorta caused by elastin (ELN) haploinsufficiency. SVAS severity varies among patients with Williams-Beuren syndrome (WBS), a rare disorder that removes one copy of ELN and 25-27 other genes. Twenty percent of children with WBS require one or more invasive and often risky procedures to correct the defect while 30% have no appreciable stenosis, despite sharing the same basic genetic lesion. There is no known medical therapy. Consequently, identifying genes that modify SVAS offers the potential for novel modifier-based therapeutics. To improve statistical power in our rare-disease cohort (N = 104 exomes), we utilized extreme-phenotype cohorting, functional variant filtration and pathway-based analysis. Gene set enrichment analysis of exome-wide association data identified increased adaptive immune system variant burden among genes associated with SVAS severity. Additional enrichment, using only potentially pathogenic variants known to differ in frequency between the extreme phenotype subsets, identified significant association of SVAS severity with not only immune pathway genes, but also genes involved with the extracellular matrix, G protein-coupled receptor signaling and lipid metabolism using both SKAT-O and RQTest. Complementary studies in Eln+/-; Rag1-/- mice, which lack a functional adaptive immune system, showed improvement in cardiovascular features of ELN insufficiency. Similarly, studies in mixed background Eln+/- mice confirmed that variations in genes that increase elastic fiber deposition also had positive impact on aortic caliber. By using tools to improve statistical power in combination with orthogonal analyses in mice, we detected four main pathways that contribute to SVAS risk.

Topics: Adolescent; Animals; Aortic Stenosis, Supravalvular; Child, Preschool; Constriction, Pathologic; Disease Models, Animal; Elastin; Exome Sequencing; Haploinsufficiency; Homeodomain Proteins; Humans; Male; Mice; Risk Factors; Williams Syndrome

High-performance athletes can develop symptomatic arterial flow restriction during exercise caused by endofibrosis. The pathogenesis is poorly understood; however, coagulation enzymes, such as tissue factor (TF) and coagulation factor Xa, might contribute to the fibrotic process, which is mainly regulated through activation of protease-activated receptors (PARs). Therefore, the aim of this explorative study was to evaluate the presence of coagulation factors and PARs in endofibrotic tissue, which might be indicative of their potential role in the natural development of endofibrosis.. External iliac arterial specimens with endofibrosis (n = 19) were collected during surgical interventions. As control, arterial segments of the external iliac artery (n = 20) were collected post mortem from individuals with no medical history of cardiovascular disease who donated their body to medical science. Arteries were paraffinized and cut in tissue sections for immunohistochemical analysis. Positive staining within lesions was determined with ImageJ software (National Institutes of Health, Bethesda, Md).. Endofibrotic segments contained a neointima, causing intraluminal stenosis, which was highly positive for collagen (+150%; P < .01) and elastin (+148%; P < .01) in comparison with controls. Intriguingly, endofibrosis was not limited to the intima because collagen (+213%) and elastin (+215%) were also significantly elevated in the media layer of endofibrotic segments. These findings were accompanied by significantly increased α-smooth muscle actin-positive cells, morphologically compatible with the presence of myofibroblasts. In addition, PAR1 and PAR4 and the membrane receptor TF were increased as well as coagulation factor X.. We showed that myofibroblasts and the accompanying collagen and elastin synthesis might be key factors in the development of endofibrosis. The special association with increased presence of PARs, factor X, and TF suggests that protease-mediated cell signaling could be a contributing component in the mechanisms leading to endofibrosis.

Topics: Adult; Aged; Aged, 80 and over; Athletes; Athletic Performance; Cadaver; Case-Control Studies; Collagen; Constriction, Pathologic; Elastin; Factor X; Female; Fibrosis; Humans; Iliac Artery; Male; Middle Aged; Myofibroblasts; Peripheral Arterial Disease; Receptor, PAR-1; Receptors, Thrombin; Thromboplastin; Up-Regulation; Vascular Remodeling; Young Adult

Williams syndrome is characterized by obstructive aortopathy attributable to heterozygous loss of. We quantified determinants of luminal stenosis in thoracic aortas of. Deficient circumferential growth is the predominant mechanism for moderate obstructive aortic disease resulting from partial elastin deficiency. Our findings suggest that diverse aortic manifestations in Williams syndrome result from graded elastin content, and SMC hyperplasia causing medial expansion requires additional elastin loss superimposed on

Topics: Adult; Animals; Aorta, Thoracic; Aortic Diseases; Cell Proliferation; Cells, Cultured; Collagen; Constriction, Pathologic; Disease Models, Animal; Elastin; Fibrosis; Genetic Predisposition to Disease; Humans; Hyperplasia; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Time Factors; Vascular Stiffness; Vasoconstriction; Williams Syndrome

Sporadic and familial elastin mutations can occur in large vessel stenosis such as supravalvular aortic stenosis and narrowing of the descending aorta. However, there are very few reports regarding the arteriopathy of cerebral, pulmonary or abdominal arteries in elastin mutations. We herein report the case of a Japanese female patient presenting with multiple arteriopathy including moyamoya disease, a tortuosity of abdominal arteries and pulmonary hypertension due to peripheral pulmonary artery stenosis. This case suggests the possible progression of cerebral arteriopathy including moyamoya disease in patients with elastin mutations. © 2016 Wiley Periodicals, Inc.

Topics: Adult; Arteries; Constriction, Pathologic; Elastin; Female; Humans; Joint Instability; Moyamoya Disease; Mutation; Phenotype; Skin Diseases, Genetic; Vascular Malformations

A hallmark feature of Williams-Beuren Syndrome (WBS) is a generalized arteriopathy due to elastin deficiency, presenting as stenoses of medium and large arteries and leading to hypertension and other cardiovascular complications. Deletion of a functional NCF1 gene copy has been shown to protect a proportion of WBS patients against hypertension, likely through reduced NADPH-oxidase (NOX)-mediated oxidative stress. DD mice, carrying a 0.67 Mb heterozygous deletion including the Eln gene, presented with a generalized arteriopathy, hypertension, and cardiac hypertrophy, associated with elevated angiotensin II (angII), oxidative stress parameters, and Ncf1 expression. Genetic (by crossing with Ncf1 mutant) and/or pharmacological (with ang II type 1 receptor blocker, losartan, or NOX inhibitor apocynin) reduction of NOX activity controlled hormonal and biochemical parameters in DD mice, resulting in normalized blood pressure and improved cardiovascular histology. We provide strong evidence for implication of the redox system in the pathophysiology of the cardiovascular disease in a mouse model of WBS. The phenotype of these mice can be ameliorated by either genetic or pharmacological intervention reducing NOX activity, likely through reduced angII-mediated oxidative stress. Therefore, anti-NOX therapy merits evaluation to prevent the potentially serious cardiovascular complications of WBS, as well as in other cardiovascular disorders mediated by similar pathogenic mechanism.

Topics: Acetophenones; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Arteries; Blood Pressure; Cardiomegaly; Constriction, Pathologic; Disease Models, Animal; Elastin; Enzyme Activation; Enzyme Inhibitors; Humans; Hypertension; Losartan; Mice; NADPH Oxidases; Oxidative Stress; Sequence Deletion; Williams Syndrome

Elastin is an essential component of vertebrate arteries that provides elasticity and stores energy during the cardiac cycle. Elastin production in the arterial wall begins midgestation but increases rapidly during the last third of human and mouse development, just as blood pressure and cardiac output increase sharply. The aim of this study is to characterize the structure, hemodynamics, and mechanics of developing arteries with reduced elastin levels and determine the critical time period where elastin is required in the vertebrate cardiovascular system. Mice that lack elastin (Eln(-/-)) or have approximately one-half the normal level (Eln(+/-)) show relatively normal cardiovascular development up to embryonic day (E) 18 as assessed by arterial morphology, left ventricular blood pressure, and cardiac function. Previous work showed that just a few days later, at birth, Eln(-/-) mice die with high blood pressure and tortuous, stenotic arteries. During this period from E18 to birth, Eln(+/-) mice add extra layers of smooth muscle cells to the vessel wall and have a mean blood pressure 25% higher than wild-type animals. These findings demonstrate that elastin is only necessary for normal cardiovascular structure and function in mice starting in the last few days of fetal development. The large increases in blood pressure during this period may push hemodynamic forces over a critical threshold where elastin becomes required for cardiovascular function. Understanding the interplay between elastin amounts and hemodynamic forces in developing vessels will help design treatments for human elastinopathies and optimize protocols for tissue engineering.

Topics: Animals; Aorta; Blood Pressure; Compliance; Constriction, Pathologic; Echocardiography, Doppler; Elastin; Gene Expression Regulation, Developmental; Gestational Age; Hemodynamics; Mechanotransduction, Cellular; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron; Muscle, Smooth, Vascular; Organogenesis; Regional Blood Flow; Stress, Mechanical; Ventricular Function, Left; Ventricular Pressure

Coronary artery angioplasty triggers healing that causes constrictive remodeling. Because collagen accumulation correlates with constrictive remodeling and aldosterone has been implicated in collagen accumulation, we examined how aldosterone and the mineralocorticoid receptor antagonists spironolactone and eplerenone affect remodeling and collagen in porcine coronary and iliac arteries after angioplasty.. Twenty-four pigs were allocated into 4 treatment groups: oral eplerenone (100 mg/d), oral spironolactone (200 mg/d), subcutaneous aldosterone (400 microgram/d), or no treatment. Twenty-eight days after angioplasty of the coronary arteries, eplerenone increased total vessel area by 30% (P<0.05) and luminal area by nearly 60% (P<0.05) compared with the no-treatment group, without affecting neointima size. These effects were accompanied by a 65% reduction in neointimal and medial collagen density (both P<0.05). Spironolactone was less effective, and aldosterone tended to exert opposite effects on coronary artery structure after angioplasty. These effects were not observed in angioplastied iliac arteries.. Eplerenone attenuates constrictive remodeling after coronary artery angioplasty by mechanisms involving reduction in collagen accumulation, which thus appears to be an important contributor to constrictive remodeling of angioplastied coronary arteries.

Topics: Aldosterone; Angioplasty, Balloon; Animals; Collagen; Constriction, Pathologic; Coronary Disease; Coronary Vessels; Elastin; Eplerenone; Iliac Artery; Male; Mineralocorticoid Receptor Antagonists; Spironolactone; Swine; Swine, Miniature; Tunica Intima

Constrictive remodeling plays a prominent role in restenosis after balloon angioplasty, but its regulation remains unclear. Because endothelial dysfunction and changes in extracellular matrix have been reported after angioplasty, this study was designed to simultaneously evaluate endothelial function and collagen and elastin changes after restenosis and arterial remodeling.. Atherosclerosis was induced in femoral arteries of 22 New Zealand White rabbits by air-desiccation and a high-cholesterol diet. One month later, angioplasty was performed. Histomorphometry and in vitro assessment of endothelial function were performed 4 weeks after angioplasty. Restenosis correlated with constrictive remodeling (r=0.60, P=0.01) but not with neointimal growth (r=-0.06, P=0.79). Restenosis correlated with an impaired relaxation to acetylcholine (ACh; r=0.61, P=0.02) but not with the response to the endothelium-independent vasodilator sodium nitroprusside (r=-0.25, P=0.40). Restenosis correlated positively with collagen accumulation (r=0.69, P=0.004) and inversely with elastin density (r=-0.48, P=0.05). Relaxations to ACh were significantly more decreased in arteries with constrictive remodeling than in those with enlargement remodeling (3.7+/-7.9% versus 35.5+/-15.0%, P=0.04). Neointimal collagen density was significantly higher in arteries with constrictive remodeling than in those with enlargement remodeling (34.5+/-4.5% versus 18.2+/-4.7%, P=0.03). Endothelial function and collagen and elastin density were independent predictors of restenosis in the study.. These results demonstrate that the severity of restenosis after angioplasty correlated with both defective endothelium-dependent relaxation and increased collagen density.

Topics: Angioplasty, Balloon; Animals; Collagen; Constriction, Pathologic; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Elastin; Endothelium, Vascular; Extracellular Matrix; Rabbits; Recurrence; Vasoconstriction

We describe an otherwise healthy 2-year-old patient with Williams syndrome who had a stroke as a result of intracranial multivessel focal and segmental stenotic disease. The diagnosis of Williams syndrome was confirmed by elastin gene deletion testing. Combined magnetic resonance imaging and magnetic resonance angiography, and transcranial Doppler flow studies, were used in diagnosing and monitoring the course of the disease.

Topics: Brain Ischemia; Cerebral Arterial Diseases; Constriction, Pathologic; Elastin; Gene Deletion; Humans; Infant; Infant, Newborn; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Ultrasonography, Doppler, Transcranial; Vascular Diseases

Remodeling of the vessel wall after balloon angioplasty injury is incompletely understood, and in particular, the role of extracellular matrix synthesis in restenosis has received little attention. The objective of the present study was to determine the sequence of changes in collagen, elastin, and proteoglycan synthesis and content after balloon injury and to relate these changes to growth of the intimal lesions and extent of cell proliferation. In a double-injury non-cholesterol-fed model, right iliac arterial lesions in 43 rabbits were treated with balloon angioplasty, and the rabbits were killed at five time points ranging from immediate to 12 weeks. Vessel wall collagen and elastin content and synthesis were measured after incubation with 14C-proline and separation with a cyanogen bromide extraction procedure. Sulfated glycosaminoglycan synthesis was measured after incubation with [35S]sulfate, papain digestion, and ethanol precipitation. Continuous in vivo infusion of bromodeoxyuridine (96 hours) was used to assess cell proliferation. The intimal area significantly increased from 0.27 +/- 0.08 to 0.73 +/- 0.11 mm2 between 0 and 12 weeks. Intimal and medial cell proliferation were modest and peaked at 1 week (labeling indexes of 4.8% and 3.0%, respectively) and then markedly declined by 2 weeks. Significant increases in collagen, elastin, and proteoglycan synthesis, up to 4 to 10 times above control nondamaged contralateral iliac arteries, were noted at 1, 2, and 4 weeks. These increases in synthesis were accompanied by significant increases in collagen and elastin content (by approximately 35%) that coincided with the temporal increase in cross-sectional area.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angioplasty, Balloon; Animals; Arteriosclerosis; Cell Division; Collagen; Constriction, Pathologic; Elastin; Extracellular Matrix; Glycosaminoglycans; Histological Techniques; Iliac Artery; Male; Rabbits; Recurrence; Time Factors; Tunica Intima; Tunica Media