Genetic Interference with Endothelial PPARg Alters Vascular Responses to Select Renin Angiotensin System (RAS) Peptides

Abstract

Pharmacological activation of the nuclear receptor peroxisome proliferator‐activated receptor‐gamma (PPARg) protects the vasculature. Much less is known regarding the impact of PPARg under physiological conditions, when driven by endogenous ligands. Recently, we found that endothelial PPARg protects against angiotensin II (Ang II)‐induced vascular dysfunction. Here, we explored that concept further examining whether effects were sex‐dependent along with underlying mechanisms. We studied transgenic mice expressing a human dominant negative mutation in PPARg driven by the endothelial specific vascular cadherin promoter (E‐V290M), using age‐matched, non‐transgenic (non‐Tg) littermates as controls. Acetylcholine (an endothelium‐dependent agonist) produced similar relaxation of carotid arteries from non‐Tg and E‐V290M mice. In contrast, incubation of isolated carotid arteries with Ang II (1 nM) overnight reduced responses to acetylcholine by about 50% in male and female E‐V290M mice but not non‐Tg controls (P<0.05). Endothelial dysfunction in E‐V290M mice was restored to normal by inhibitors of superoxide (tempol), NADPH oxidase (VAS‐2870), Rho kinase (ROCK 1 and ROCK2, Y‐27632), ROCK2 (SLX‐2119), NF‐kB (NEMO‐binding domain peptide), or IL‐6 (neutralizing antibody). Responses in non‐Tg mice were not affected by these inhibitors. We next hypothesized that in addition to vascular effects of Ang II, PPARg may influence components of the angiotensin 1‐7 (Ang 1‐7) arm of the RAS. In the basilar artery, vasodilation to Ang 1‐7 was reduced in E‐V290M mice by more than 50% under baseline conditions (while responses to acetylcholine were minimally affected), an effect that was reversed by Y‐27632. Thus, effects of Ang II on vascular function are augmented by interference with endothelial PPARg through mechanisms that are sex‐independent but involve interrelated oxidant‐inflammatory signaling and Rho kinase (ROCK2). The study provides the first evidence that endothelial PPARg interacts with components of the Ang 1‐7 arm of the RAS. These cell‐specific roles for PPARg have implications for vascular pathophysiology and therapeutic approaches for vascular disease.Support or Funding InformationThis work was supported by the NIH, the Department of Veterans Affairs, and the Fondation Leducq.