Peroxisome Proliferator–Activated Receptor Regulates Angiotensin II–Stimulated Phosphatidylinositol 3-Kinase and Mitogen-Activated Protein Kinase in Blood Vessels In Vivo

Angiotensin (Ang) II is implicated in hypertension, vascular remodeling, and insulin resistance. Peroxisome proliferator–activated receptor (PPAR) activators increase insulin sensitivity and improve Ang II–induced vascular remodeling. We evaluated the effects of the PPARactivator rosiglitazone on Ang II signaling in aorta and mesenteric arteries. Rats received Ang II by subcutaneous infusion and/or rosiglitazone per os for 7 days. Blood pressure rise in Ang II–infused rats was attenuated by rosiglitazone. Ang II significantly increased Ang II type 1 receptor expression in the mesenteric arteries (P 0.001), whereas that of the aorta was decreased (P 0.05), changes which were reversed by rosiglitazone. Akt activity was increased by Ang II and returned to basal levels under rosiglitazone in both vascular beds. However, Ang II–induced extracellular signal–regulated kinase 1/2 activity increased in aorta but not in mesenteric vessels (P 0.001), where 4E-binding protein 1 activity was significantly increased by Ang II and inhibited by PPARactivation. In response to Ang II, Src homology (SH) 2–containing inositol phosphatase 2 activity was increased (P 0.05) in both vascular beds. In conclusion, PPARactivator rosiglitazone attenuated Ang II–induced blood pressure elevation and intracellular signaling on aorta and mesenteric vessels. There was differential inhibition of Ang II type 1 receptor receptors/phosphatidylinositol 3-kinase/Akt and extracellular signal–regulated kinase 1/2 in both vessels. Effects of PPARactivators on these pathways could contribute to regression of vascular remodeling in models of hypertension and diabetes and, accordingly, in hypertensive diabetic patients. (Hypertension. 2006;47:102-108.)