Disruption of endothelial peroxisome proliferator-

26 Vascular endothelial cells express the ligand-activated transcription factor, peroxisome 27 proliferator-activated receptor gamma (PPARγ), which participates in regulation of 28 metabolism, cell proliferation, and inflammation. PPARγ ligands attenuate, while loss of 29 function mutations in PPARγ stimulate, endothelial dysfunction suggesting that PPARγ 30 may regulate vascular endothelial nitric oxide production. To explore the role of 31 endothelial PPARγ in regulation of vascular nitric oxide production in vivo, mice 32 expressing Cre recombinase driven by an endothelial-specific promoter were crossed 33 with mice carrying a floxed PPARγ gene to produce endothelial PPARγ null mice 34 (ePPARγ-/-). Compared to littermate controls, ePPARγ-/animals were hypertensive at 35 baseline and demonstrated comparable increases in systolic blood pressure in 36 response to angiotensin II infusion. Compared to control animals, aortic ring relaxation 37 responses to acetylcholine were impaired whereas relaxation responses to sodium 38 nitroprusside were unaffected in ePPARγ-/mice. Similarly, intact aortic segments from 39 ePPARγ-/mice released less nitric oxide than controls, whereas endothelial nitric oxide 40 synthase expression was similar in control and ePPARγ-/aortas. Reduced nitric oxide 41 production in ePPARγ-/aortas was associated with an increase in parameters of 42 oxidative stress in the blood and activation of nuclear factor-kappa B (NF-κB) in aortic 43 homogenates. These findings demonstrate that endothelial PPARγ regulates vascular 44 nitric oxide production, and that disruption of endothelial PPARγ contributes to 45 endothelial dysfunction in vivo. 46