Tie2-mediated loss of peroxisome proliferator-activated receptor-γ in mice causes PDGF receptor-β-dependent pulmonary arterial muscularization

Guignabert C, Alvira CM, Alastalo T-P, Sawada H, Hansmann G, Zhao M, Wang L, El-Bizri N, Rabinovitch M. Tie2-mediated loss of peroxisome proliferator-activated receptor-gamma in mice causes PDGF receptor-beta-dependent pulmonary arterial muscularization. Am J Physiol Lung Cell Mol Physiol 297: L1082-L1090, 2009. First published October 2, 2009; doi:10.1152/ajplung.00199.2009.-Peroxisome proliferator-activated receptor (PPAR)-gamma is reduced in pulmonary arteries (PAs) of patients with PA hypertension (PAH), and we reported that deletion of PPAR gamma in smooth muscle cells (SMCs) of transgenic mice results in PAH. However, the sequelae of loss of PPAR gamma in PA endothelial cells (ECs) are unknown. Therefore, we bred Tie2-Cre mice with PPAR gamma(flox/flox) mice to induce EC loss of PPAR gamma (Tie2 PPAR gamma(-/-)), and we assessed PAH by right ventricular systolic pressure (RVSP), RV hypertrophy (RVH), and muscularized distal PAs in room air ( RA), after chronic hypoxia (CH), and after 4 wk of recovery in RA (Rec-RA). The Tie2 PPAR gamma(-/-) mice developed spontaneous PAH in RA with increased RVSP, RVH, and muscularized PAs vs. wild type (WT); both genotypes exhibited a similar degree of PAH following chronic hypoxia, but Tie2 PPAR gamma(-/-) mice had more residual PAH compared with WT mice after Rec-RA. The Tie2 PPAR gamma(-/-) vs. WT mice in RA had increased platelet-derived growth factor receptor-beta (PDGF-R beta) expression and signaling, despite an elevation in the PPAR gamma target apolipoprotein E, an inhibitor of PDGF signaling. Inhibition of PDGF-R beta signaling with imatinib, however, was sufficient to reverse the PAH observed in the Tie2 PPAR gamma(-/-) mice. Thus the disruption of PPAR gamma signaling in EC is sufficient to cause mild PAH and to impair recovery from CH-induced PAH. Inhibition of heightened PDGF-R beta signaling is sufficient to reverse PAH in this genetic model.