Vascular remodeling is the fundamental basis for hypertensive disease, in which vascular smooth muscle cell (VSMC) dysfunction plays an essential role. Previous studies suggest that the activation of peroxisome proliferator-activated receptor α (PPARα) by fibrate drugs has cardiovascular benefits independent of the lipid-lowering effects. However, the underlying mechanism remains incompletely understood. This study explored the role of PPARα in angiotensin II (Ang II)-induced vascular remodeling and hypertension using VSMC-specific Ppara-deficient mice. The PPARα expression was markedly downregulated in the VSMCs upon Ang II treatment. A PPARα deficiency in the VSMC significantly aggravated the Ang II-induced hypertension and vascular stiffness, with little influence on the cardiac function. The morphological analyses demonstrated that VSMC-specific Ppara-deficient mice exhibited an aggravated vascular remodeling and oxidative stress. In vitro, a PPARα deficiency dramatically increased the production of mitochondrial reactive oxidative species (ROS) in Ang II-treated primary VSMCs. Finally, the PPARα activation by Wy14643 improved the Ang II-induced ROS production and vascular remodeling in a VSMC PPARα-dependent manner. Taken together, these data suggest that PPARα plays a critical protective role in Ang II-induced hypertension via attenuating ROS production in VSMCs, thus providing a potential therapeutic target for hypertensive diseases.
