Role of Vascular Smooth Muscle Cell Phenotype Switching in Arteriogenesis

Abstract

Arteriogenesis is one of the primary physiological means by which the circulatory collateral system restores blood flow after significant arterial occlusion in peripheral arterial disease patients. Vascular smooth muscle cells (VSMCs) are the predominant cell type in collateral arteries and respond to altered blood flow and inflammatory conditions after an arterial occlusion by switching their phenotype between quiescent contractile and proliferative synthetic states. Maintaining the contractile state of VSMC is required for collateral vascular function to regulate blood vessel tone and blood flow during arteriogenesis, whereas synthetic SMCs are crucial in the growth and remodeling of the collateral media layer to establish more stable conduit arteries. Timely VSMC phenotype switching requires a set of coordinated actions of molecular and cellular mediators to result in an expansive remodeling of collaterals that restores the blood flow effectively into downstream ischemic tissues. This review overviews the role of VSMC phenotypic switching in the physiological arteriogenesis process and how the VSMC phenotype is affected by the primary triggers of arteriogenesis such as blood flow hemodynamic forces and inflammation. Better understanding the role of VSMC phenotype switching during arteriogenesis can identify novel therapeutic strategies to enhance revascularization in peripheral arterial disease.

Keywords: arteriogenesis; collateral arteries; peripheral arterial disease; phenotypic switch; vascular smooth muscle cell.

Figure 1

Pathophysiology of arteriogenesis. (A) Diagram illustrates the hemodynamic changes of collateral circulation after arterial occlusion. Pressure-gradient (ΔP); blood flow (Q); direction of blood flow (arrows); fluid shear stress (σ_(shear)); circumferential wall stress or tension (σ_(circ)). (B) Cross-section of collateral arteries showing the different phases of the physiological arteriogenesis (IEL: internal elastic lamina). The presented time course of arteriogenesis phases is observed in the mouse model of limb ischemia. (C) The dynamics of the vascular smooth muscle cell (VSMC) phenotype switch during arteriogenesis. Oscillatory shear stress (σ_(shear)). The figure has been created with BioRender.com.

Figure 2

Molecular regulation of vascular smooth muscle phenotype. TGFβ induces the formation of pSMAD2/3-SMAD4 complex, which is translocated into the nucleus, where it binds to SMAD-binding elements (SBE), leading to the expression of early contractile SMC genes. The SMAD interaction with myocardin (MYOCD) or MRTFs enforces SMC differentiation and maturation. Rho/ROCK activates the actin polymerization, which release G-actin monomers from MRTFs, enabling MRTFs to translocate into the nucleus. There, they bind to the SRF/CArG, inducing the expression of SMC contractile genes. IGF activates the PI3 K/AKT signaling pathway that phosphorylates the nuclear FOXO4 facilitating the nuclear export of FOXO4 to release the repression on the CArG/SRF/MYOCD complex. Growth factors (e.g., FGF, PDGF, EGF) through the MEK/ERK pathway represses SMC contractile genes by phosphorylation of the ternary complex factor (TCF) Elk-1 and MRTFs, and by increasing KLF4 level. Phospho-Elk-1 abolishes the SRF interaction with MYOCD or induces SRF-dependent transcription of early growth genes. The phosphorylation of MRTFs prevents their translocation into the nucleus. The figure has been created with BioRender.com.