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This Article Full Text Full Text (PDF) All Versions of this Article: 288/6/L1162    most recent 00180.2004v1 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 ISI Web of Science 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 ISI Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Jankov, R. P. Articles by Tanswell, A. K. Search for Related Content PubMed PubMed Citation Articles by Jankov, R. P. Articles by Tanswell, A. K.

A role for platelet-derived growth factor -receptor in a newborn rat model of endothelin-mediated pulmonary vascular remodeling

¹Clinical Integrative Biology, Sunnybrook & Women's Research Institute, Toronto; ²Lung Biology Programme, The Hospital for Sick Children Research Institute, Toronto; and Departments of ³Pediatrics and ⁴Physiology, University of Toronto, Toronto, Ontario, Canada

Submitted 18 May 2004 ; accepted in final form 17 February 2005

Newborn rats exposed to 60% O₂ for 14 days develop endothelin (ET)-1-dependent pulmonary hypertension with vascular remodeling, characterized by increased smooth muscle cell (SMC) proliferation and medial thickening of pulmonary resistance arteries. Using immunohistochemistry and Western blot analyses, we examined the effect of exposure to 60% O₂ on expression in the lung of receptors for the platelet-derived growth factors (PDGF), which are implicated in the pathogenesis of arterial smooth muscle hyperplasia. We observed a marked O₂-induced upregulation of PDGF- and - receptors (PDGF-R and -R) on arterial smooth muscle. This led us to examine pulmonary vascular PDGF receptor expression in 60% O₂-exposed rats given SB-217242, a combined ET receptor antagonist, which we found prevented the O₂-induced upregulation of PDGF-R, but not PDGF-R, on arterial smooth muscle. PDGF-BB, a major PDGF-R ligand, was found to be a potent in vitro inducer of hyperplasia and DNA synthesis in cultured pulmonary artery SMC from infant rats. A critical role for PDGF-R ligands in arterial SMC proliferation was confirmed in vivo using a truncated soluble PDGF-R intervention, which attenuated SMC proliferation induced by exposure to 60% O₂. Collectively, these data are consistent with a major role for PDGF-R-mediated SMC proliferation, acting downstream of increased ET-1 in a newborn rat model of 60% O₂-induced pulmonary hypertension.

pulmonary oxygen toxicity; vascular smooth muscle; growth factors; soluble receptors

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