HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: 297/6/L1082    most recent 00199.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Guignabert, C. Articles by Rabinovitch, M. Search for Related Content PubMed PubMed Citation Articles by Guignabert, C. Articles by Rabinovitch, M.

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

¹Cardiopulmonary Research Program, Vera Moulton Wall Center for Pulmonary Vascular Disease, and ; Departments of ²Pediatrics (Cardiology) and ; ³Medicine, Stanford University School of Medicine, Stanford, California

Submitted 15 June 2009 ; accepted in final form 29 September 2009

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

endothelial cells; platelet-derived growth factor receptor-β; pulmonary remodeling; smooth muscle cell; platelet-derived growth factor

This article has been cited by other articles:

				B. B. Graham, M. M. Mentink-Kane, H. El-Haddad, S. Purnell, L. Zhang, A. Zaiman, E. F. Redente, D. W. H. Riches, P. M. Hassoun, A. Bandeira, et al. Schistosomiasis-Induced Experimental Pulmonary Hypertension: Role of Interleukin-13 Signaling Am. J. Pathol., September 1, 2010; 177(3): 1549 - 1561. [Abstract] [Full Text] [PDF]

				R. L. Sutliff, B.-Y. Kang, and C. M. Hart PPAR{gamma} as a potential therapeutic target in pulmonary hypertension Therapeutic Advances in Respiratory Disease, June 1, 2010; 4(3): 143 - 160. [Abstract] [PDF]

				G. Hansmann and M. Rabinovitch The protective role of adiponectin in pulmonary vascular disease Am J Physiol Lung Cell Mol Physiol, January 1, 2010; 298(1): L1 - L2. [Full Text] [PDF]

				G. Hansmann and R. T. Zamanian PPAR{gamma} Activation: A Potential Treatment For Pulmonary Hypertension Science Translational Medicine, December 23, 2009; 1(12): 12ps14 - 12ps14. [Full Text] [PDF]