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. 2009 Dec;297(6):L1082-90. doi: 10.1152/ajplung.00199.2009. Epub 2009 Oct 2.


Peroxisome proliferator-activated receptor (PPAR)-gamma is reduced in pulmonary arteries (PAs) of patients with PA hypertension (PAH), and we reported that deletion of PPARgamma in smooth muscle cells (SMCs) of transgenic mice results in PAH. However, the sequelae of loss of PPARgamma in PA endothelial cells (ECs) are unknown. Therefore, we bred Tie2-Cre mice with PPARgamma(flox/flox) mice to induce EC loss of PPARgamma (Tie2 PPARgamma(-/-)), 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 PPARgamma(-/-) 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 PPARgamma(-/-) mice had more residual PAH compared with WT mice after Rec-RA. The Tie2 PPARgamma(-/-) vs. WT mice in RA had increased platelet-derived growth factor receptor-beta (PDGF-Rbeta) expression and signaling, despite an elevation in the PPARgamma target apolipoprotein E, 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 the disruption of PPARgamma signaling in EC is sufficient to cause mild PAH and to impair recovery from CH-induced PAH. Inhibition of heightened PDGF-Rbeta signaling is sufficient to reverse PAH in this genetic model.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Air
  • Animals
  • Apolipoproteins E / metabolism
  • Blood Pressure
  • Cell Separation
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation
  • Heart Ventricles / pathology
  • Heart Ventricles / physiopathology
  • Humans
  • Hypertension, Pulmonary / complications
  • Hypertension, Pulmonary / pathology
  • Hypertension, Pulmonary / physiopathology
  • Hypertrophy
  • Hypoxia / complications
  • Mice
  • Myocytes, Smooth Muscle / enzymology
  • Myocytes, Smooth Muscle / pathology*
  • PPAR gamma / deficiency*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Pulmonary Artery / diagnostic imaging
  • Pulmonary Artery / enzymology
  • Pulmonary Artery / pathology*
  • Pulmonary Artery / physiopathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Receptor, TIE-2
  • Signal Transduction
  • Ultrasonography


  • Apolipoproteins E
  • PPAR gamma
  • RNA, Messenger
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Platelet-Derived Growth Factor beta
  • Receptor, TIE-2
  • Tek protein, mouse
  • Extracellular Signal-Regulated MAP Kinases