Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2018-2019)

It is critical to understand the molecular mechanisms underlying the regulation of vascular functions. The medial layers of blood vessels are composed of smooth muscle cells (SMCs), which perform the contractile functions of blood vessels, arteries in particular. The differentiation of vascular SMCs and their associated contractile functions are under the control of myocardin, a master transcriptional co-factor that activates the transcription of genes that encode smooth muscle-specific contractile proteins. During aging and the onset of age-related vascular pathologies, vascular SMCs undergo phenotypic conversion, which is associated with loss of the differentiated/contractile phenotype, and concomitant acquisition of a synthetic phenotype, including enhanced proliferation, motility and secretion capacity. Importantly, loss of myocardin expression and activity correlates with phenotypic conversion of vascular SMCs. Targeting myocardin or related molecular cascades could be a promising intervention approach for vascular diseases. We and other groups have pioneered exploration of the signaling pathways through which myocardin regulates differentiation and proliferation of SMCs, but the in-depth molecular actions of myocardin remain elusive.

It is widely accepted that the differentiation of vascular SMCs requires a coordinated process orchestrated by myocardin and serum response factor (SRF). However, we have reported that myocardin can repress SMC proliferation through both SRF-dependent and -independent pathways, and our preliminary studies demonstrate that the pro-contractile functions of myocardin remain detectable when SRF is depleted, suggesting an SRF-independent mechanism for myocardin to promote the contractile phenotype. Therefore, in this proposal, we will investigate a novel, SRF-independent signaling pathway of myocardin in the regulation of vascular SMC differentiation.

We will dissect the relative contribution of SRF-dependent and -independent pathways to myocardin-induced differentiation of SMCs. We will study the potential involvement of NF-κB, a potent stimulator of SMC proliferation, which is repressed by myocardin in an SRF-independent manner in SMC differentiation. We will also study if c-Myc, a reported downstream target gene of NF-κB and a dominant transcriptional factor that promotes cell proliferation, contributes to SRF-independent differentiation induced by myocardin. Moreover, we will assess the role of myocardin, and the NF-κB/c-Myc cascade, in reciprocal inhibition of proliferation and differentiation of SMCs. We anticipate that our proposed studies will provide novel insights into the molecular control of differentiation and contractile phenotypes of vascular SMCs, which will serve as knowledge base for exploration of new therapeutic targets in vascular diseases.