Abstract 504: Tie2-Mediated Loss of Peroxisome Proliferator-Activated Receptor-γ in Transgenic Mice Increases Platelet Derived Growth Factor-Receptor β and Pulmonary Arterial Muscularization
Peroxisome Proliferator-Activated Receptor (PPAR)-γ is reduced in pulmonary arteries (PA) of PA hypertension (PAH) patients, and we reported that deletion of PPARγ in smooth muscle cells (SMCs) of transgenic mice results in PAH. However, the sequelae of loss of PPARγ in PA-endothelial cells (ECs) is unknown. Therefore, we generated mice with targeted deletion of endothelial-PPARγ using a Tie2-promoter (Tie2 PPARγ−/−), and assessed PAH by right ventricular systolic pressure (RVSP), RV hypertrophy (RVH), and muscularized distal PAs in room air (RA), following chronic hypoxia (CH), and after 4 weeks recovery in RA (Rec-RA). The Tie2 PPARγ−/− vs. WT mice had increased RVSP, RVH and muscularized PAs in RA. While CH did not produce more severe PAH in the transgenic mice, Rec-RA was associated with a persistent increase in PAH severity as compared to WT controls. Evaluating PPARγ targets, we found that the deletion increased caveolin-1 and endothelial nitric oxide synthase (eNOS), but did not change NO production. However apolipoprotein (Apo)E, a PPARγ target in Tie2-expressing macrophages was reduced in Tie2 PPARγ−/− lungs. ApoE decreased PDGF-Rβ expression in cultured PA-SMCs, and conversely, reduced ApoE in Tie2 PPARγ−/− vs. WT mice was associated with heightened PDGF-Rβ expression and signaling localized largely to PA-SMCs. Furthermore, PDGF-Rβ inhibition with imatinib reversed the features of PAH in Tie2 PPARγ−/− mice. PDGF-Rβ was elevated in both genotypes after CH consistent with similar PAH, but did not explain persistent PAH in Rec-RA. Thus Tie2-mediated loss of PPARγ causing spontaneous PAH by a non cell-autonomous increase in SMC PDGF-Rβ expression and signaling.