Marlene Rabinovitch
Publication Details
-
Tie2-Mediated Loss of Peroxisome Proliferator-Activated Receptor-{gamma} in Mice Causes PDGF-Receptor {beta}-Dependant Pulmonary Arterial Muscularization.
Am J Physiol Lung Cell Mol Physiol. 2009Peroxisome proliferators activated receptor (PPAR)-gamma is reduced in pulmonary arteries (PA) of PA hypertension (PAH) patients, and we reported that deletion of PPARgamma in smooth muscle cells (SMC) of transgenic mice results in PAH. However, the sequelae of loss of PPARgamma in PA-endothelial cells (EC), is unknown. Therefore, we bred Tie2-Cre mice with PPARgammaflox/flox mice to induce EC loss of PPARgamma (Tie2 PPARgamma-/-), 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 of recovery in RA (Rec-RA). The Tie2 PPARgamma-/- mice developed spontaneous PAH in RA with increased RVSP, RVH and muscularized PAs vs. WT; both genotypes exhibited a similar degree of PAH following chronic hypoxia, but Tie2 PPARgamma-/- mice had more residual PAH as compared to wild-type mice after Rec-RA. The Tie2 PPARgamma-/- vs. WT mice in RA, had increased platelet derived growth factor receptor (PDGF-R)beta expression and signaling, despite elevation in the PPARgamma target, apolipoprotein-E (ApoE), an inhibitor of PDGF signaling. Inhibition of PDGF-Rbeta signaling with imatinib, however, was sufficient to reverse the PAH observed in the Tie2 PPARgamma-/- mice. Thus, disruption of PPARgamma signaling in EC is sufficient to cause mild PAH, and impaired recovery from CH-induced PAH, and inhibition of heightened PDGF-Rbeta signaling may play a key role in the development of PAH. Key words: Pulmonary Arterial Hypertension, Endothelial cells, Peroxisome Proliferator-Activated Receptor- (PPAR), Platelet-Derived Growth Factor-Receptor beta (PDGF-R).
Help