Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension

Abstract

The phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a pivotal role in hypertension-induced vascular changes including vascular remodeling. The precise mechanisms underlying VSMC phenotypic modulation remain elusive. Here we test the role of peroxisome proliferator-activated receptor (PPAR)-␥ in the VSMC phenotypic modulation during hypertension. Both spontaneously hypertensive rat (SHR) aortas and SHR-derived VSMCs exhibited reduced PPAR-␥ expression and excessive VSMC phenotypic modulation identified by reduced contractile proteins, ␣-smooth muscle actin (␣-SMA) and smooth muscle 22␣ (SM22␣), and enhanced proliferation and migration. PPAR-␥ overexpression rescued the expression of ␣-SMA and SM22␣, and inhibited the proliferation and migration in SHR-derived VSMCs. In contrast, PPAR-␥ silencing exerted the opposite effect. Activating PPAR-␥ using rosiglitazone in vivo up-regulated aortic ␣-SMA and SM22␣ expression and attenuated aortic remodeling in SHRs. Increased activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling was observed in SHR-derived VSMCs. PI3K inhibitor LY294002 rescued the impaired expression of contractile proteins, and inhibited proliferation and migration in VSMCs from SHRs, whereas constitutively active PI3K mutant had the opposite effect. Overexpression or silencing of PPAR-␥ inhibited or excited PI3K/Akt activity, respectively. LY294002 counteracted the PPAR-␥ silencing induced proliferation and migration in SHR-derived VSMCs, whereas active PI3K mutant had the opposite effect. In contrast, reduced proliferation and migration by PPAR-␥ overexpression were reversed by the active PI3K mutant, and further inhibited by LY294002. We conclude that PPAR-␥ inhibits VSMC phenotypic modulation through inhibiting PI3K/Akt signaling. Impaired PPAR-␥ expression is responsible for VSMC phenotypic modulation during hypertension. These findings highlight an attractive therapeutic target for hypertension-related vascular disorders.Hypertension and hypertension-induced vascular remodeling underlie numerous cardiovascular disorders. Activated vascular smooth muscle cells (VSMCs) 2 are essential contributors to this vascular remodeling (1). Unlike other muscle cells, VSMCs do not terminally differentiate. They can switch from a differentiated phenotype (also known as contractile or quiescent phenotype) to a dedifferentiated phenotype (also known as synthetic or activated phenotype) in response to vascular injury. In this process, VSMCs regain their proliferative and migratory capacities, secrete matrix proteins, and down-regulate smooth muscle contractile proteins, such as ␣-smooth muscle actin (␣-SMA), smooth muscle 22␣ (SM22␣), smooth muscle myosin heavy chain, and calponin (2). Although this phenotypic modulation is undoubtedly required for vascular repair, inappropriate modulation is associated with increased vascular resistance and aggravates vascular injury. However, despite intensive research efforts, the precise mechanisms underlying VSMC phenotypic modula...

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