Abstract 663: Loss of Peroxisome Proliferator-Activated Receptor-gamma in Endothelial Cells Causes Pulmonary Arterial Hypertension in Transgenic Mice
Introduction: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a nuclear receptor expressed in endothelial cells (EC) and known to regulate enzymes important in vascular dilatation and angiogenesis such as endothelial nitric oxide synthase (eNOS) and heme oxygenase-1 (HO-1). Expression of PPAR-gamma is reduced in the pulmonary arteries (PA) of patients with severe PA hypertension (PAH).
Objective: We therefore investigated whether loss of PPAR-gamma in EC might cause PAH under normoxic conditions or might worsen the severity of PAH induced by chronic hypoxia.
Materials and Methods: We generated transgenic mice with targeted deletion of PPAR-gamma in ECs by breeding a mouse expressing Cre under the regulation of the Tie2 promoter with a mouse in which critical exons of PPAR-gamma were flanked by LoxP sites. We compared right ventricular systolic pressure (RVSP), RV hypertrophy (RV/LV+S), in Tie2CrePPAR-gammaflox/flox and wild type littermate controls (WT) in normoxia and following 3 weeks of chronic hypoxia (CH) (10 mice per group, 5 per gender) and also assessed muscularization of distal pulmonary vessels and number of peripheral arteries in CH.
Results: Tie2CrePPAR-gammaflox/flox vs. WT mice had mildly elevated RVSP (24.6 vs 21.56mmHg) and RVH during normoxia (P <0.01 for both) with similar systemic blood pressures. However the RVSP following CH was similar in Tie2CrePPAR-gammaflox/flox and WT mice (28.1mmHg vs 28.5mmHg) as was RVH and muscularizaton of distal vessels, and number of arteries relative to alveoli.
Conclusions: Thus loss of PPAR-gamma in ECs appears to result in mild pulmonary vasoconstricton, and while not exacerbated during chronic hypoxia, this feature may have an impact on recovery during return to normoxia, if EC production of eNOS and HO-1 are necessary for regression of vascular disease.