Vascular smooth muscle cells in Marfan syndrome aneurysm: the broken bricks in the aortic wall

Perrucci, Gianluca Lorenzo; Rurali, Erica; Gowran, Aoife; Pini, Alessandro; Antona, Carlo; Chiesa, Roberto; Pompilio, Giulio; Nigro, Patrizia

doi:10.1007/s00018-016-2324-9

Cited by 44 publications

(34 citation statements)

References 100 publications

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“…In normal human body, contractile phenotype of VSMCs plays an important role in maintenance of the vascular structure and function of the blood vessel wall. When TAD occurred, the number and rate of synthetic VSMCs are reported to be obviously increased, resulting in decreased aortic elasticity and rupture of blood vessel wall [21–23]. These studies indicated that phenotype switch of SMCs may become a crucial factor implicated into the occurrence of TAD.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible factor 1a induces phenotype switch of human aortic vascular smooth muscle cell through PI3K/AKT/AEG-1 signaling

et al. 2017

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To date, hypoxia-inducible factor 1a (HIF-1a) and astrocyte elevated gene-1 (AEG-1) have been involved in the proliferation, migration and morphological changes of vascular smooth muscle cells. However, the potential relationship of HIF-1a-AEG-1 pathway in human aortic smooth muscle cell (HASMC) has not been reported. In the present study, in-vitro assays were utilized to explore the potential impact of HIF-1a-AEG-1 signaling on HASMC phenotype. Here, we found that HIF-1a expression was up-regulated in the media of thoracic aortic dissection tissues as compared with normal aortic tissues, and was associated with increased apoptotic SMCs and decreased AEG-1 expression. Mechanically, hypoxia promoted the expression of HIF-1a by PI3K-AKT pathway in HASMCs; HIF-1a further suppressed the expressions of AEG-1, a-SMA and SM22a, and promoted osteopontin (OPN) expression. Functionally, HIF-1a inhibited the proliferation and migration of HASMCs. However, si-HIF-1a or Akt inhibitor abrogated HIF-1a-mediated related expressions and biological effects above. In conclusion, HIF-1a induces HASMC phenotype switch, and closely related to PI3K/AKT and AEG-1 signaling, which may provide new avenues for the prevention and treatment of aortic dissection diseases.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible factor 1a induces phenotype switch of human aortic vascular smooth muscle cell through PI3K/AKT/AEG-1 signaling

et al. 2017

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“…The TGF-β pathway’s multi-functional role results in many context- and tissue-dependent functions, which are difficult to unravel (Pardali et al, 2010). Most studies on diseases of the great arteries have aimed to understand the role of TGF-β in SMCs (Li et al, 2014; Yang et al, 2016; Zhang et al, 2016; Perrucci et al, 2017; Takeda et al, 2018), overlooking its function in the endothelium. In EC biology, Alk5 function has been mostly studied in vitro , where it has been shown to maintain EC quiescence (Goumans et al, 2002; Goumans et al, 2003; Lebrin et al, 2004; van Meeteren and ten Dijke, 2012; Maring et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract

Boezio

Bensimon-Brito

Piesker

et al. 2020

Preprint

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19The development of the cardiac outflow tract (OFT), which connects the heart to the great 20 arteries, relies on a complex crosstalk between endothelial (ECs) and smooth muscle (SMCs) 21 cells. Defects in OFT development can lead to severe malformations, including aortic 22 aneurysms, which have often been associated with impaired TGF-β signaling. To further 23 investigate the role of TGF-β signaling in OFT formation, we generated zebrafish lacking the 24 type I TGF-β receptor Alk5 and found a strikingly specific dilation of the OFT. alk5 mutants 25 also exhibit increased EC numbers, extracellular matrix (ECM) and SMC disorganization. 26 Surprisingly, endothelial-specific alk5 overexpression in alk5 mutants rescues both 27 endothelial and SMC defects. Furthermore, modulation of the ECM gene fibulin-5, a TGF-β 28 target, partially restores OFT morphology and function. These findings reveal a new 29 requirement for endothelial TGF-β signaling in OFT morphogenesis and suggest an important 30 role for the endothelium in the etiology of aortic malformations.31 32

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“…CVDs include a series of diseases affecting blood vessels, such as coronary artery disease, aortic aneurysms, cerebrovascular disease, peripheral artery disease, pulmonary hypertension and renal artery stenosis, as well as diseases affecting the heart. Vascular smooth muscle cells (VSMCs) are one of the foremost cellular types of vascular walls that regulate arterial vascular tone and maintain structural stability for blood flow together with elastic fibers [2,3]. In response to environmental changes, modulation of VSMC survival and function plays a crucial role in the development of CVDs.…”

Section: Introductionmentioning

confidence: 99%

EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation

Chen¹,

Hu²,

Huo³

et al. 2020

Int. J. Biol. Sci.

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Although EHMT2 (also known as G9a) plays a critical role in several kinds of cancers and cardiac remodeling, its function in vascular smooth muscle cells (VSMCs) remains unknown. In the present study, we revealed a novel function of EHMT2 in regulating autophagic cell death (ACD) of VSMC. Inhibition of EHMT2 by BIX01294 or knockdown of EHMT2 resulted in reduced VSMC numbers which were independent of proliferation and apoptosis. Interestingly, EHMT2 protein levels were significantly decreased in VSMCs treated with autophagic inducers. Moreover, more autophagic vacuoles and accumulated LC3II were detected in VSMCs treated with BIX01294 or lenti-shEHMT2 than their counterparts. Furthermore, we found that EHMT2 inhibited the ACD of VSMCs by suppressing autophagosome formation. Mechanistically, the pro-autophagic effect elicited by EHMT2 inhibition was associated with SQSTM1 and BECN1 overexpression. Moreover, these detrimental effects were largely nullified by SQSTM1 or BECN1 knockdown. More importantly, similar results were observed in primary human aortic VSMCs. Overall, these findings suggest that EHMT2 functions as a crucial negative regulator of ACD via decreasing SQSTM1 or BECN1 expression and that EHMT2 could be a potent therapeutic target for cardiovascular diseases (e.g., aortic dissection).

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Vascular smooth muscle cells in Marfan syndrome aneurysm: the broken bricks in the aortic wall

Cited by 44 publications

References 100 publications

Hypoxia-inducible factor 1a induces phenotype switch of human aortic vascular smooth muscle cell through PI3K/AKT/AEG-1 signaling

Hypoxia-inducible factor 1a induces phenotype switch of human aortic vascular smooth muscle cell through PI3K/AKT/AEG-1 signaling

Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract

EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation

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