Impaired vascular function in transgenic mice with smooth muscle cell specific dominant negative hPPARγ expression.

PPARγ is a ligand activated transcription factor. Dominant negative (DN) mutations in PPARγ have been reported in patients with type 2 diabetes and early onset hypertension. To explore the role of PPARγ in vascular smooth muscle cells (vSMC) in vivo, we generated transgenic (Tg) mice designed to interfere with PPARγ-dependent signaling by specifically targeting expression of a DN PPARγ (P467L) to SMC. Transgene expression in tissues containing SMC, including aorta was confirmed by RNase protection. Vascular function in aorta from Tg mice and non-Tg (NT) littermates was examined in vitro. Remarkably, aorta of Tg animals exhibited endothelial dysfunction and an impaired response to nitric oxide as evidenced by significantly lower relaxation to acetylcholine (ACh 10µM, 9±2%) and sodium nitroprusside (SNP 10µM, 44±4%) than aorta of NT (38±3% for ACh, 864-1% for SNP, P<0.001). Submaximal relaxation to the endothelial-independent vasodilator paperverine was slightly but significantly impaired. We are currently testing if the impaired response to NO is due to impaired cGMP-dependent signaling. Interestingly, aorta of Tg mice also contracted considerably more to endothelin-1 (ET-1 0.1 µM, 302±29 mg) than did aorta of NT (44±6 mg, P<0.001). This increase in contraction was inhibited by the ET-A receptor antagonist BQ-123. These data suggest that vSMC PPARγ plays a pivotal role in the regulation of vascular tone. [ABSTRACT FROM AUTHOR]