Regulation of the Phenotypic Switch of Vascular Smooth Muscle Cells by Adiponectin

Abstract

Vascular smooth muscle cells (VSMCs) play an essential role in the development and progression of atherosclerosis. The phenotypic switch from contractile to synthetic cells induces excess proliferation and migration of VSMCs into the intima contributing to plaque formation. Adiponectin (Adpn) is an adipokine that regulates glucose metabolism through AMPK and plays beneficial roles in atherosclerosis. We hypothesize that Adpn promotes the contractile phenotype of VSMC reducing proliferation and migration of VSMCs, a process that is protective against plaque formation.Differentiation, proliferation, and signaling through AMPK‐dependent pathways were assessed in VSMCs isolated from aortas of wild type (WT) and Adpn−/− mice. Proliferation markers, including cyclin D1, were increased in Adpn−/− cells, and AMPK activity and differentiation markers were reduced. Cells were analyzed for matrix metalloproteinases (MMPs) which are responsible for extracellular matrix (ECM) remodeling, a contributing factor to the VSMC phenotypic switch. We found that MMP protein expression and activity, measured by zymography, were reduced in Adpn−/− cells. To test whether the phenotypic switch is regulated by AMPK, we treated cells with Metformin, an AMPK activator, or AdipoRon, an activator of Adpn receptors. Metformin and AdipoRon reduced Cyclin D1 and MAPK signaling in Adpn−/− cells, suggesting that AMPK prevents VSMC proliferation; however, none of the treatments yielded an effect on markers of differentiation.These data illustrated that Adpn regulates proliferation through an AMPK‐dependent signaling pathway, while regulating differentiation by an AMPK‐independent mechanism. The role of MMPs in VSMC differentiation in response to Adpn remains to be elucidated.