WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

Carthy, Jon M.; Luo, Zongshu; McManus, Bruce M.

doi:10.1038/labinvest.2011.164

Cited by 20 publications

(27 citation statements)

References 51 publications

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“…28,47,48 Likewise, endosialin has been found to promote atherosclerosis through phenotypic remodeling of vascular SMCs. 31 In accord with CXCL12 driving WNT signaling, we confirmed that both CXCL12 and WNT3a promoted the contractile phenotype of SMCs in vitro , 49 consistent with our observations upon Cxcr4 -deficiency in vivo . Combined with a reduced macrophage cholesterol efflux capacity due to lower ApoA1 serum levels, this may underlie atherogenic effects of Cxcr4 -deficiency in SMCs.…”

Section: Discussionsupporting

confidence: 88%

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Döring¹,

Noels²,

Vorst³

et al. 2017

Circulation

146

147

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Background The CXCL12/CXCR4 chemokine ligand/receptor axis controls (progenitor) cell homeostasis and trafficking. So far, an atheroprotective role of CXCL12/CXCR4 has only been implied through pharmacological intervention, particularly as the somatic deletion of the CXCR4 gene in mice is embryonically lethal. Moreover, cell-specific effects of CXCR4 in the arterial wall and underlying mechanisms remain elusive, prompting us to investigate the relevance of CXCR4 in vascular cell types for atheroprotection. Methods We examined the role of vascular CXCR4 in atherosclerosis and plaque composition by inducing an endothelial cell (EC, BmxCreERT2-driven)-specific or smooth muscle cell (SMC, SmmhcCreERT2- or TaglnCre-driven)-specific-deficiency of CXCR4 in an apolipoprotein E-deficient mouse model. To identify underlying mechanisms for effects of CXCR4, we studied endothelial permeability, intravital leukocyte adhesion, involvement of the Akt/WNT/β-catenin signaling pathway and relevant phosphatases in VE-cadherin expression and function, vascular tone in aortic rings, cholesterol efflux from macrophages, and expression of SMC phenotypic markers. Finally, we analyzed associations of common genetic variants at the CXCR4 locus with the risk for coronary heart disease, along with CXCR4 transcript expression in human atherosclerotic plaques. Results The cell-specific deletion of CXCR4 in arterial ECs (n=12-15) or SMCs (n=13-24) markedly increased atherosclerotic lesion formation in hyperlipidemic mice. Endothelial barrier function was promoted by CXCL12/CXCR4, which triggered Akt/WNT/β-catenin-signaling to drive VE-cadherin expression and stabilized junctional VE-cadherin complexes through associated phosphatases. Conversely, endothelial CXCR4-deficiency caused arterial leakage and inflammatory leukocyte recruitment during atherogenesis. In arterial SMCs, CXCR4 sustained normal vascular reactivity and contractile responses, whereas CXCR4-deficiency favored a synthetic phenotype, the occurrence of macrophage-like SMCs in the lesions, and impaired cholesterol efflux. Regression analyses in humans (n=259,796) identified the C-allele at rs2322864 within the CXCR4 locus to be associated with increased risk for coronary heart disease. In line, C/C risk genotype carriers showed reduced CXCR4 expression in carotid artery plaques (n=188), which was furthermore associated with symptomatic disease. Conclusions Our data clearly establish that vascular CXCR4 limits atherosclerosis by maintaining arterial integrity, preserving endothelial barrier function, and a normal contractile SMC phenotype. Enhancing these beneficial functions of arterial CXCR4 by selective modulators might open novel therapeutic options in atherosclerosis.

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Section: Discussionsupporting

confidence: 88%

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Döring¹,

Noels²,

Vorst³

et al. 2017

Circulation

146

147

View full text Add to dashboard Cite

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“…Gal-3 can also induce the migration of macrophage in mouse (27). Atherosclerosis is characterized by the activation and accumulation of smooth muscle cells in the intimal layer of blood vessels where they internalized a lot of lipids (28). The enhanced proliferation and migration of smooth muscle cells are the symbol of the early pathology of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Galectin-3 induces the phenotype transformation of human vascular smooth muscle cells via the canonical Wnt signaling

Tian

Chen

Cao

et al. 2017

Molecular Medicine Reports

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Galectin‑3, a galactoside‑binding protein, is highly expressed in carotid plaques and plays an important role in the atherosclerotic lesions. The phenotype transformation of vascular smooth muscle cells is the basic pathological change of atherosclerosis. This study investigated the effects of exogenous galectin‑3 on the function and phenotype transformation of human umbilical vascular smooth muscle cells (HUSMC). In this study, we treated vascular smooth muscle cells with recombinant galectin‑3 and tested its effect on cell proliferation, migration, and phenotype transformation. Our results showed that exogenous galectin‑3 promoted human umbilical vascular smooth muscle cells (HUSMC) proliferation and migration. Exogenous galectin‑3 enhanced the expression of the smooth muscle synthetic protein osteopontin, smooth muscle contractile proteins calponin and smooth muscle α‑actin. The galectin‑3‑induced change in cell phenotype was associated with the activation of canonical Wnt signaling, as measured by β‑catenin axin2 and cyclin D1 expression. β‑catenin inhibition by small interfering RNA reduced cell proliferation, decreased cell motility, and blocked galectin‑3‑induced phenotype transformation of human umbilical vascular smooth muscle cells (HUSMC). Our data suggest galectin‑3 promotes the phenotype transformation of human umbilical vascular smooth muscle cells (HUSMC) by activating Wnt/β‑catenin signaling pathway.

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“…fibronectin, laminin, collagen) was downregulated, and the majority of these genes, especially those encoding Ar, α-SMA and fibronectin, have been reported as downstream targets of Wnt/β-catenin signaling (Carthy et al, 2012;De Langhe et al, 2005;Gradl et al, 1999;Hlubek et al, 2001;Yang et al, 2002;Yang et al, 2006). We speculated that Wnt/β-catenin signaling is functioning in PMCs and that the activity of this pathway is impaired in Lgr4 mutant PMCs, as Lgr4 has recently been demonstrated to be one of the receptors for R-spondins, which amplify Wnt signaling (Carmon et al, 2011;de Lau et al, 2011;Glinka et al, 2011;Hao et al, 2012).…”

Section: Lgr4 Modulates Wnt/β-catenin Signaling In Pmcsmentioning

confidence: 99%

Lgr4-mediated Wnt/β-catenin signaling in peritubular myoid cells is essential for spermatogenesis

Liu

Guan

et al. 2013

Development

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SUMMARYPeritubular myoid cells (PMCs) are myofibroblast-like cells that surround the seminiferous tubules and play essential roles in male fertility. How these cells modulate spermatogenesis and the signaling pathways that are involved are largely unknown. Here we report that Lgr4 is selectively expressed in mouse PMCs in the testes, and loss of Lgr4 leads to germ cells arresting at meiosis I and then undergoing apoptosis. In PMCs of Lgr4 mutant mice, the expression of androgen receptor, alpha-smooth muscle actin and extracellular matrix proteins was dramatically reduced. Malfunctioning PMCs further affected Sertoli cell nuclear localization and functional protein expression in Lgr4 −/− mice. In addition, Wnt/β-catenin signaling was activated in wild-type PMCs but attenuated in those of Lgr4 −/− mice. When Wnt/β-catenin signaling was reactivated by crossing with Apc min/+ mice or by Gsk3β inhibitor treatment, the Lgr4 deficiency phenotype in testis was partially rescued. Together, these data demonstrate that Lgr4 signaling through Wnt/β-catenin regulates PMCs and is essential for spermatogenesis.

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WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

Cited by 20 publications

References 51 publications

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Galectin-3 induces the phenotype transformation of human vascular smooth muscle cells via the canonical Wnt signaling

Lgr4-mediated Wnt/β-catenin signaling in peritubular myoid cells is essential for spermatogenesis

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