Smooth muscle cells (SMCs) are a critical component of blood vessel walls that provide structural support, regulate vascular tone, and allow for vascular remodeling. These cells also exhibit a remarkable plasticity that contributes to vascular growth and repair but also to cardiovascular pathologies, including atherosclerosis, intimal hyperplasia and restenosis, aneurysm, and transplant vasculopathy. Mouse models have been an important tool for the study of SMC functions. The development of smooth muscle-expressing Cre -driver lines has allowed for exciting discoveries, including recent advances revealing the diversity of phenotypes derived from mature SMC transdifferentiation in vivo using inducible CreER T2 lines. We review SMC-targeting Cre lines driven by the Myh11, Tagln , and Acta2 promoters, including important technical considerations associated with these models. Limitations that can complicate study of the vasculature include expression in visceral SMCs leading to confounding phenotypes, and expression in multiple nonsmooth muscle cell types, such as Acta2-Cre expression in myofibroblasts. Notably, the frequently employed Tagln / SM22 α- Cre driver expresses in the embryonic heart but can also confer expression in nonmuscular cells including perivascular adipocytes and their precursors, myeloid cells, and platelets, with important implications for interpretation of cardiovascular phenotypes. With new Cre -driver lines under development and the increasing use of fate mapping methods, we are entering an exciting new era in SMC research.

Objective The adipocyte-secreted hormone adiponectin exerts important cardioprotective and anti-diabetic effects. Little is known about its effect on vascular smooth muscle cells (VSMC), key cells in restenosis, hypertension, and atherosclerosis. Methods and Results Using human coronary artery VSMC, we report that recombinant adiponectin in the HMW or trimeric, but not globular forms induces VSMC differentiation through a mechanism similar to the classic feedback signaling employed by rapamycin, a drug known to effectively inhibit restenosis on drug-eluting stents (DES). Using a combination of pharmacologic agents, siRNA, and overexpression approaches, we demonstrate that adiponectin activates 5′ AMP-activated protein kinase (AMPKα2), leading to inhibition of mammalian target of rapamycin complex 1 (mTORC1) and S6K1. This in turn stabilizes IRS-1, driving Akt2 -mediated inhibition of FoxO4 and subsequent contractile protein induction. While adiponectin and rapamycin have similarly beneficial effects on VSMC phenotype in both cell and organ culture, a direct comparison of the effects of rapamycin versus adiponectin on endothelial cells (EC) revealed distinct differences: rapamycin inhibited, while adiponectin maintained, Akt phosphorylation. Importantly, Akt activity preserves endothelial function. Conclusions Adiponectin promotes VSMC differentiation and preserves EC Akt signaling, suggesting that targeting the adiponectin pathway may have advantages over rapamycin in developing new DES therapeutics.

This review addresses the complexity of coronary collateral growth from the aspect of redox signaling and introduces the concept of a ''redox window'' in the context of collateral growth. In essence, the redox window constitutes a range in the redox state of cells, which not only is permissive for the actions of growth factors but also amplifies their actions. The interactions of redox-dependent signaling with growth factors are well established through the actions of many redox-dependent kinases (e.g., Akt and p38 mitogen-activated protein kinase). The initial changes in cellular redox can be induced by a variety of events, from the oxidative burst during reperfusion after ischemia, to recruitment of various types of inflammatory cells capable of producing reactive oxygen species.

Adiponectin is a cardioprotective adipokine derived predominantly from visceral fat. We recently demonstrated that exogenous adiponectin induces vascular smooth muscle cell (VSMC) differentiation via repression of mTORC1 and FoxO4. Here we report for the first time that VSMC express and secrete adiponectin, which acts in an autocrine and paracrine manner to regulate VSMC contractile phenotype. Adiponectin was found to be expressed in human coronary artery and mouse aortic VSMC. Importantly, siRNA knock-down of endogenous adiponectin in VSMC significantly reduced the expression of VSMC contractile proteins. Contractile protein deficiency was also observed in primary VSMC isolated from Adiponectin-/- mice. This deficiency could be rescued by culturing Adiponectin-/- VSMC in conditioned media from wild type (WT) VSMC. Moreover, the paracrine effect of VSMC-derived adiponectin was confirmed as adiponectin neutralizing antibody blocked the rescue. Overexpressed adiponectin also exerted paracrine effects on neighboring untransfected VSMC, which was also blocked by adiponectin neutralizing antibody. Interestingly, adiponectin expression was inducible by the PPARγ agonist rosiglitazone. Our data support an important role for VSMC-derived adiponectin in maintaining VSMC contractile phenotype, contributing to critical cardioprotective functions in the vascular wall.