Submitted on June 15, 2009
Revised on September 4, 2009
Accepted on September 29, 2009
Tie2-Mediated Loss of Peroxisome Proliferator-Activated Receptor-
in Mice Causes PDGF-Receptor 
-Dependant Pulmonary Arterial Muscularization
Christophe Guignabert1, Cristina M. Alvira1, Tero-Pekka Alastalo, Hirofumi Sawada1, Georg Hansmann2, Mingming Zhao1, Lingli Wang1, Nesrine El-Bizri1, and Marlene Rabinovitch3*
1 Stanford University
2 HArvard University
3 Stanford University, School of Medicine
* To whom correspondence should be addressed. E-mail: marlener{at}stanford.edu.
Peroxisome proliferators activated receptor (PPAR)-
is reduced in pulmonary arteries (PA) of PA hypertension (PAH) patients, and we reported that deletion of PPAR in smooth muscle cells (SMC) of transgenic mice results in PAH. However, the sequelae of loss of PPAR in PA-endothelial cells (EC), is unknown. Therefore, we bred Tie2-Cre mice with PPARflox/flox mice to induce EC loss of PPAR (Tie2 PPAR-/-), 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 PPAR-/- 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 PPAR-/- mice had more residual PAH as compared to wild-type mice after Rec-RA. The Tie2 PPAR-/- vs. WT mice in RA, had increased platelet derived growth factor receptor (PDGF-R)
expression and signaling, despite elevation in the PPAR target, apolipoprotein-E (ApoE), an inhibitor of PDGF signaling. Inhibition of PDGF-R signaling with imatinib, however, was sufficient to reverse the PAH observed in the Tie2 PPAR-/- mice. Thus, disruption of PPAR signaling in EC is sufficient to cause mild PAH, and impaired recovery from CH-induced PAH, and inhibition of heightened PDGF-R signaling may play a key role in the development of PAH.
