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Does BMPR2 Mutation Disrupt Pulmonary Vasculogenesis?^*

^* From the Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, UK.

Correspondence to: Nicholas W. Morrell, MD, Division of Respiratory Medicine, Department of Medicine, Box 157, Addenbrooke’s Hospital, Hills Rd, Cambridge, CB2 2QQ, UK; e-mail: nwm23{at}cam.ac.uk

Mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR2) cause familial primary pulmonary hypertension, although the precise mechanism remains obscure. We previously found that expression of BMPR-II is predominantly localized to endothelial cells in lung tissue. In addition, mice deficient in the bone morphogenetic protein (BMP)-restricted signaling intermediary, Smad5, exhibit defects in angiogenesis. To begin to clarify the role of BMP signaling in pulmonary vasculogenesis/angiogenesis, we studied the expression of BMP-2/BMP-4, BMPR2, Smad1, and phospho-Smad1 in developing human embryos and fetuses.

We found that expression of BMPs, BMPR2, and phospho-Smad1 in the lung were increased at the time of maximal expansion of the fetal capillary vascular bed. In cultured human pulmonary artery endothelial cells (HPAECs), we confirmed expression of transforming growth factor-ß superfamily type I (activin receptor-like kinase 1 to activin receptor-like kinase 6) and all type II receptors by reverse transcriptase-polymerase chain reaction. Functionally, HPAECs exhibited increased ³H-thymidine incorporation and protection against apoptosis in response to BMP-4 (0.1 to 100 ng/mL). In addition, BMP-4 led to phosphorylation of Smad1 and activation of p38-mitogen activated protein kinase. In cell migration assays, BMP-2, BMP-4, and BMP-7 markedly increased endothelial cell migration at low concentrations of ligand (0.1 ng/mL). HPAECs transfected with adenoviral mutant BMPR2 constructs are being used to assess the impact of mutations on cell migration.

These results suggest that BMP signaling may be critical during the development of pulmonary circulation. Disruption of these signaling pathways may predispose to abnormal pulmonary vascular development, setting the stage for the later development of familial primary pulmonary hypertension.

	Footnotes

 
Abbreviations: BMP = bone morphogenetic protein; BMPR2 = bone morphogenetic protein type II receptor; HPAEC = human pulmonary artery endothelial cell

This Article Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jeffery, T. K. Articles by Morrell, N. W. Search for Related Content PubMed PubMed Citation Articles by Jeffery, T. K. Articles by Morrell, N. W.