Disruption of endothelial peroxisome proliferator-activated receptor-γ reduces vascular nitric oxide production

Vascular endothelial cells express the ligand-activated transcription factor, peroxisome proliferator-activated receptor-γ (PPARγ), which participates in the regulation of metabolism, cell proliferation, and inflammation. PPARγ ligands attenuate, whereas the loss of function mutations in PPARγ stimulate, endothelial dysfunction, suggesting that PPARγ may regulate vascular endothelial nitric oxide production. To explore the role of endothelial PPARγ in the regulation of vascular nitric oxide production in vivo, mice expressing Cre recombinase driven by an endothelial-specific promoter were crossed with mice carrying a floxed PPARγ gene to produce endothelial PPARγ null mice (ePPARγ−/−). When compared with littermate controls, ePPARγ−/− animals were hypertensive at baseline and demonstrated comparable increases in systolic blood pressure in response to angiotensin II infusion. When compared with those of control animals, aortic ring relaxation responses to acetylcholine were impaired, whereas relaxation responses to sodium nitroprusside were unaffected in ePPARγ−/− mice. Similarly, intact aortic segments from ePPARγ−/− mice released less nitric oxide than those from controls, whereas endothelial nitric oxide synthase expression was similar in control and ePPARγ−/− aortas. Reduced nitric oxide production in ePPARγ−/− aortas was associated with an increase in the parameters of oxidative stress in the blood and the activation of nuclear factor-κB in aortic homogenates. These findings demonstrate that endothelial PPARγ regulates vascular nitric oxide production and that the disruption of endothelial PPARγ contributes to endothelial dysfunction in vivo

Rosiglitazone Attenuates Chronic Hypoxia–Induced Pulmonary Hypertension in a Mouse Model

Chronic hypoxia contributes to pulmonary hypertension through complex mechanisms that include enhanced NADPH oxidase expression and reactive oxygen species (ROS) generation in the lung. Stimulation of peroxisome proliferator–activated receptor γ (PPARγ) reduces the expression and activity of NADPH oxidase. Therefore, we hypothesized that activating PPARγ with rosiglitazone would attenuate chronic hypoxia–induced pulmonary hypertension, in part, through suppressing NADPH oxidase–derived ROS that stimulate proliferative signaling pathways. Male C57Bl/6 mice were exposed to chronic hypoxia (CH, FiO2 10%) or room air for 3 or 5 weeks. During the last 10 days of exposure, each animal was treated daily by gavage with either the PPARγ ligand, rosiglitazone (10 mg/kg/d) or with an equal volume of vehicle. CH increased: (1) right ventricular systolic pressure (RVSP), (2) right ventricle weight, (3) thickness of the walls of small pulmonary vessels, (4) superoxide production and Nox4 expression in the lung, and (5) platelet-derived growth factor receptor β (PDGFRβ) expression and activity and reduced phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression. Treatment with rosiglitazone prevented the development of pulmonary hypertension at 3 weeks; reversed established pulmonary hypertension at 5 weeks; and attenuated CH-stimulated Nox4 expression and superoxide production, PDGFRβ activation, and reductions in PTEN expression. Rosiglitazone also attenuated hypoxia-induced increases in Nox4 expression in pulmonary endothelial cells in vitro despite hypoxia-induced reductions in PPARγ expression. Collectively, these findings indicate that PPARγ ligands attenuated hypoxia-induced pulmonary vascular remodeling and hypertension by suppressing oxidative and proliferative signals providing novel insights for mechanisms underlying therapeutic effects of PPARγ activation in pulmonary hypertension