Peroxisome proliferator activated receptors (PPAR's) are ligand activated transcription fact5ores which have a pleiotropic role in many physiological processes. PPARgamma (g) is the molecular target of the thiazolidinemediones class of drugs which are used to treat patients with non-insulin dependent diabetes mellitus (NIDDM). Endothelial dysfunction, which develops in patients that are diabetic or chronically hypertensive, is thought to contribute to the progression of carotid artery disease, cerebral vascular dysfunction and stroke. PPARg is expressed in vascular endothelium and smooth muscle and therefore is a potentially important factor in the regulation of vascular function and blood pressure. PPARg has been reported to inhibit responses to vasoconstrictors such as endothelin, stimulate the release of vasodilators, and increase expression of CuZn-SOD in vascular muscle and endothelium. Additionally, treatment with thiazolidinediones has been reported to lower blood pressure in patients with NIDDM. Moreover, patients carrying dominant negative mutations in PPARg exhibit early onset type II diabetes and hypertension. Current data suggests that PPARg exerts a protective effect in the vessel wall. We hypothesize that PPARg plays an important role in the regulation of vascular function and blood pressure. We will test this hypothesis using transgenic and viral transfer technologies, in order to gain new insight into PPARg's physiological and pathophysiological role in the carotid artery and cerebral circulation. To test this hypothesis, we will 1) test whether PPARg activation improves endothelial function and lowers blood pressure in a transgenic mouse model with established endothelial dysfunction and hypertension, 2) use adenoviruses over-expressing wildtype and dominant negative mutations of PPARg in carotid arteries from normotensive and hypertensive mice to test whether than can alter endothelial function, and 3) generate novel transgenic mice with expression of the wild-type and dominant negative mutants of PPARg targeted specifically to vascular muscle and endothelial cells using cell- specific promoters. We will characterize vascular function in these models to gain a better understanding of PPARg role in the vasculature both under the normal and diseased conditions.
Showing the most recent 10 out of 432 publications
