Spontaneous arterial dissection: phenotype and molecular pathogenesis

Grond‐Ginsbach, Caspar; Pjontek, Rastislav; Aksay, Suna Su; Hyhlik‐Dürr, A.; Böckler, Dittmar; Groß-Weißmann, Marie-Luise

doi:10.1007/s00018-010-0276-z

Cited by 47 publications

(40 citation statements)

References 151 publications

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“…Mutations were identified in a variety of genes (COL3A1, COL1A1, COL5A2, TGFBR2, TGFBR1, ACTA2) in a minority of the patients, whereas the search for mutation remained without positive results in the majority of analyzed CeAD-patients. 24 Mutations in FBN1, COL3A1, MYH11, ACTA2, TGFBR1 and TGFBR2 were found in patients with aortic dissection, particularly in familial cases, but no mutations were detected in the majority of sporadic patients. 24 A recent study identified various rare CNVs in patients with aortic dissections, disrupting different genetic processes, in particular affecting vascular smooth muscle adhesion and contractility.…”

Section: Discussionmentioning

confidence: 99%

“…24 Mutations in FBN1, COL3A1, MYH11, ACTA2, TGFBR1 and TGFBR2 were found in patients with aortic dissection, particularly in familial cases, but no mutations were detected in the majority of sporadic patients. 24 A recent study identified various rare CNVs in patients with aortic dissections, disrupting different genetic processes, in particular affecting vascular smooth muscle adhesion and contractility. 9 A large deletion encompassing the COL3A1/COL5A2 locus was identified in another patient with aortic dissection.…”

Section: Discussionmentioning

confidence: 99%

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Copy number variation in patients with cervical artery dissection

et al. 2012

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Copy number variation in patients with cervical artery dissection

et al. 2012

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“…[11]). Of course, although carotid arteries dissect [49], it is the thoracic aorta that is most vulnerable [50]. Hence, although the present results should hold qualitatively for any elastic artery, our use of data from the mouse carotid was dictated primarily by the availability of relevant data.…”

Section: Discussionmentioning

confidence: 99%

Computational modelling suggests good, bad and ugly roles of glycosaminoglycans in arterial wall mechanics and mechanobiology

Roccabianca

Bellini

Humphrey

2014

J. R. Soc. Interface.

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The medial layer of large arteries contains aggregates of the glycosaminoglycan hyaluronan and the proteoglycan versican. It is increasingly thought that these aggregates play important mechanical and mechanobiological roles despite constituting only a small fraction of the normal arterial wall. In this paper, we offer a new hypothesis that normal aggregates of hyaluronan and versican pressurize the intralamellar spaces, and thereby put into tension the radial elastic fibres that connect the smooth muscle cells to the elastic laminae, which would facilitate mechanosensing. This hypothesis is supported by novel computational simulations using two complementary models, a mechanistically based finite-element mixture model and a phenomenologically motivated continuum hyperelastic model. That is, the simulations suggest that normal aggregates of glycosaminoglycans/proteoglycans within the arterial media may play equally important roles in supporting (i.e. a structural role) and sensing (i.e. an instructional role) mechanical loads. Additional simulations suggest further, however, that abnormal increases in these aggregates, either distributed or localized, may over-pressurize the intralamellar units. We submit that these situations could lead to compromised mechanosensing, anoikis and/or reduced structural integrity, each of which represent fundamental aspects of arterial pathologies seen, for example, in hypertension, ageing and thoracic aortic aneurysms and dissections.

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“…Concomitant with this phenotypic change, a variety of SMC differentiation-specific genes, including SM myosin heavy chain (SM-MHC), calponin, SM22␣, SM ␣-actin, and smoothelin, are reduced (4,5). SMC phenotypic switching is believed to play a key role in many cardiovascular diseases, such as hypertension, atherosclerosis, coronary heart diseases, postangioplasty restenosis, and transplantation arteriopathy (4,6,7).…”

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Specificity Protein-1 as a Critical Regulator of Human Cystathionine γ-Lyase in Smooth Muscle Cells

Yang

Pei

Teng

et al. 2011

Journal of Biological Chemistry

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Cystathionine ␥-lyase (CSE) is the major enzyme in vascular smooth muscle cells (SMCs) that catalyzes the endogenous production of H 2 S. Phenotypic switching of SMCs is affected by endogenous H 2 S level and alterations of this switching may result in vascular disorders. To date, the mechanisms underlying the alteration of CSE expression and H 2 S production in vascular proliferative diseases have been unclear. In the present study, we found that serum deprivation induced SMC differentiation marker gene expressions and increased CSE expression and H 2 S production in cultured human aorta SMCs (HASMCs). Carotid artery ligation in mice resulted in enhanced neointima formation and down-regulation of CSE expression, suggesting an important role of CSE in SMC differentiation. Transient transfection of HASMCs with human CSE (hCSE) promoter/ luciferase reporter revealed that the region between ؊226 to ؉140 base pair contains the core promoter for the hCSE gene. Deletion and mutation analysis demonstrated that two specificity protein-1 (Sp1) consensus binding sites were present in the core promoter region of the hCSE gene. Incubation of HASMCs with Sp1 binding inhibitor mithramycin inhibited CSE mRNA expression in a dose-dependent manner. Overexpression of Sp1 alone was sufficient to increase the activity of the hCSE core promoter and CSE protein expression. Chromatin immunoprecipitation assay showed that the binding of Sp1 to the hCSE promoter was increased in differentiated HASMCs compared with that in proliferated HASMCs. Exogenously applied H 2 S at 100 M stimulated SMC differentiation, which was reversed by p38 MAPK inhibitor SB203580. These results suggest that transcript factor Sp1 is a critical regulator of the hCSE expression during SMC differentiation, and CSE/H 2 S system is essential for maintenance of SMC phenotype. Vascular smooth muscle cells (SMCs)2 are highly specialized cells whose contractile status regulates blood vessel tone, blood pressure, and blood flow (1, 2). Vascular SMCs can alternate their phenotypes from contractile (differentiated) to synthetic (proliferated) phenotypes in response to extracellular cues (1-3). Concomitant with this phenotypic change, a variety of SMC differentiation-specific genes, including SM myosin heavy chain (SM-MHC), calponin, SM22␣, SM ␣-actin, and smoothelin, are reduced (4, 5). SMC phenotypic switching is believed to play a key role in many cardiovascular diseases, such as hypertension, atherosclerosis, coronary heart diseases, postangioplasty restenosis, and transplantation arteriopathy (4, 6, 7).In recent years, hydrogen sulfide (H 2 S) has emerged as a novel and important gasotransmitter for the cardiovascular system (8 -10). CSE is the major H 2 S-producing enzyme in vascular tissues, and abnormal metabolism and functions of the CSE/H 2 S pathway have been linked to various cardiovascular diseases, including atherosclerosis and hypertension (9, 11, 12). CSE expression and H 2 S production were reduced during the development of atherosclerotic plaque in apolip...

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Spontaneous arterial dissection: phenotype and molecular pathogenesis

Cited by 47 publications

References 151 publications

Copy number variation in patients with cervical artery dissection

Copy number variation in patients with cervical artery dissection

Computational modelling suggests good, bad and ugly roles of glycosaminoglycans in arterial wall mechanics and mechanobiology

Specificity Protein-1 as a Critical Regulator of Human Cystathionine γ-Lyase in Smooth Muscle Cells

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