Articles |

Does BMPR2 Mutation Disrupt Pulmonary Vasculogenesis?* FREE TO VIEW

Trina K. Jeffery, PhD; Paul D. Upton, PhD; X. Yang, PhD; M. Southwood, BSc; L. Long, PhD; R. C. Trembath, FRCP; Nicholas W. Morrell, MD
Author and Funding Information

*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@cam.ac.uk

Chest. 2005;128(6_suppl):602S. doi:10.1378/chest.128.6_suppl.602S
Text Size: A A A
Published online

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-β 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.

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




Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543