PPARγ in endothelial cells influences high fat diet-induced hypertension

Background: Peroxisome proliferator-activated receptor gamma (PPAR gamma) ligands improve human hypertension. However, the mechanism and site of this effect remains unknown, confounded by PPAR gamma expression in many cell types, including endothelial cells (ECs). Methods: To evaluate the vascular role of PPAR gamma we used a conditional null mouse model. Specific disruption of PPAR gamma in ECs was created by crossing Tie2-Cre+ transgenic (T2T+) and PPAR gamma-floxed (fl/fl) mice to generate PPAR gamma (fl/fl)T2T+ (PPARy E-null) mice. Conscious 8- to 12-week-old congenic PPAR gamma (fl/fl)Cre-(wild type) and PPAR gamma E-null mice were examined for changes in systolic blood pressure (BP) and heart rate (HR), untreated, after 2 months of salt-loading (drinking water), and after treatment for 3 months with high fat (HF) diet alone or supplemented during the last 2 weeks with rosiglitazone (3 mg/kg/d). Results: Untreated PPAR gamma E-nulls were phenotypically indistinguishable from wild-type littermates. However, compared to similarly treated wild types, HF-treated PPAR gamma E-nulls had significantly elevated systolic BP not seen after normal diet or salt-loading. Despite sex-dependent baseline differences, salt-loaded and HF-treated PPAR gamma E-nulls of either sex had significantly elevated HR versus wild types. Interestingly, rosiglitazone improved serum insulin levels, but not HF diet-induced hypertension, in PPAR gamma E-null mice. Conclusions: These results suggest that PPAR gamma in ECs not only is an important regulator of hypertension and HR under stressed conditions mimicking those arising in type 2 diabetics, but also mediates the antihypertensive effects of rosiglitazone. These data add evidence supporting a beneficial role for PPAR-gamma-specific ligands in the treatment of hypertension, and suggest therapeutic strategies targeting ECs may prove useful. (c) 2005 American Journal of Hypertension, Ltd.