Control of Phenotypic Plasticity of Smooth Muscle Cells by Bone Morphogenetic Protein Signaling through the Myocardin-related Transcription Factors

Abstract

In response to vascular injury, smooth muscle cells (SMCs) 2 exhibit a phenotypic change characterized by loss of contractility and abnormal proliferation, migration, and matrix secretion. This "synthetic" phenotype plays an active role in repair of the vascular damage. Upon resolution of the injury, local environmental signals within the vessel prompt SMCs to reacquire their "contractile" phenotype. SMC phenotype modulation contributes to the pathogenesis of numerous cardiovascular disorders, including PAH, post-angioplasty restenosis and atherosclerosis (1). Idiopathic PAH is a rare disease typically fatal because of right ventricular failure. PAH is characterized by elevated pulmonary vascular resistance and pulmonary arterial pressure with increased muscularization of small arteries, thickening or fibrosis of the intima, and the presence of plexiform lesions (2, 3). Proliferation and dedifferentiation of SMCs appear to be the major events in the formation of lesions found in pulmonary arteries of patients with PAH (2, 3). Several lines of evidence implicate the BMP pathway in the etiology of PAH. First, heterozygous mutations in the gene encoding BMPRII, the type II subunit of the BMP receptor, were identified in patients with both familial and sporadic PAH (4, 5). Furthermore, the presence of BMPRII mutations in PAH patients curtails the available therapeutic options, as the patients affected are unlikely to demonstrate vasoreactivity and respond to longterm therapy with calcium channel blockers (6, 7). Second, loss of expression of either the type I (8) or the type II subunit (9, 10) of the BMP receptor has been observed in sporadic or secondary forms of PAH. Third, transgenic mice expressing a catalytically inactive BMPRII mutant in SMCs are predisposed to develop PAH in response to different stimuli (11,12). Fourth, experimental induction of PAH in rodents via hypoxia or monocrotaline injection correlates with a down-regulation of either the type I or the type II BMP receptor and with a general repression of BMP signaling (13-15). Despite these overwhelming correlations, the etiological mechanism of action of the BMP signaling pathway in PAH remains unclear.BMPs represent the largest group in the transforming growth factor ␤ (TGF␤) superfamily of growth factors (16 -18). During embryonic development, the BMP pathway plays multiple essential roles in the induction of ventral mesoderm, cardiac myogenesis, and vasculogenesis (19). Targeted inactivation of the BMP signal transducers Smad1 and Smad5 display a severe vascular phenotype (20). However, the effects of BMPs on adult VSMCs are not completely understood. It has been reported that BMPs inhibit proliferation and induce apoptosis in serumstarved pulmonary artery smooth muscle cells (PASMC) (10,21). It is also known that BMP7 stimulates the maintenance of the SMC phenotype in aortic SMCs, while BMP2 and BMP4 appear to have opposing effects on expression of SMC-specific genes in . These results suggest that the effects of BMP signaling on VSMCs are compl...

The Amiloride Derivative Phenamil Attenuates Pulmonary Vascular Remodeling by Activating NFAT and the Bone Morphogenetic Protein Signaling Pathway

“…Phenamil, benzamil, amiloride, and cyclosporine (CsA) were purchased from Sigma and solubilized in dimethyl sulfoxide (DMSO). The cells were treated under starvation conditions (0.2% FBS) as described previously (20).…”

“…In vSMCs, TGF-␤ and BMP have been shown to promote the contractile phenotype and inhibit switching to the synthetic phenotype (20). Both TGF-␤s and BMPs inhibit vSMC proliferation and migration and increase contractile vSMC gene expression (16,20,22). Loss-of-function mutations of the genes encoding receptors of TGF-␤s and BMPs have been linked to vascular disorders, such as idiopathic PAH (IPAH) and hereditary hemorrhagic telangiectasia (41).…”

“…In vSMCs, TGF-␤ and BMP have been shown to promote the contractile phenotype and inhibit switching to the synthetic phenotype (20). Both TGF-␤s and BMPs inhibit vSMC proliferation and migration and increase contractile vSMC gene expression (16,20,22).…”

Calorie Restriction Curbs Proinflammation That Accompanies Arterial Aging, Preserving a Youthful Phenotype

“…These VSMC phenotypic shifts are driven by a coordinated repression/activation of contractile markers SM22α, α‐SMA, and myocardin 28, 29. Notably, myocardin is a key specific transcriptional coactivator of α‐SMA 29…”

Atorvastatin Inhibits Myocardin Expression in Vascular Smooth Muscle Cells

“…In addition, it was reported that activation of the RhoA-ROCK pathway by KCl through voltage-gated Ca 2ϩ channels upregulates the gene expression of myocardin and its target genes responsible for SM contractility in cultured vascular SM cells (SMCs). 10,11 Myocardin, a coactivator of serum response factor, 12 is necessary and sufficient for the vascular SMC contractile phenotype. 13,14 ATV, the most widely prescribed lipid-lowering drug, 15 was reported to inhibit the RhoA-ROCK pathway and attenuated the expression of myocardin and SM ␣-actin in human …”