Circulation Research. 2004
Published online before print March 18, 2004, doi: 10.1161/01.RES.0000126047.82846.20
Published online before print March 18, 2004, doi: 10.1161/01.RES.0000126047.82846.20
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Submitted on November 13, 2003
Revised on March 5, 2004
Accepted on March 9, 2004
Pulmonary Hypertension in Transgenic Mice Expressing a Dominant-Negative BMPRII Gene in Smooth Muscle
James West ;
From the University of Colorado Health Sciences Center, Center for Genetic Lung Disease, Division of Pulmonary Sciences and Critical Care Medicine and Department of Anesthesia, Denver, Colo; Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, Tenn; and the Department of Pathology, Johns Hopkins University, Baltimore, Md.
* To whom correspondence should be addressed. E-mail: david.rodman{at}uchsc.edu.
Bone morphogenetic peptides (BMPs), a family of cytokines critical to normal development, were recently implicated in the pathogenesis of familial pulmonary arterial hypertension. The type-II receptor (BMPRII) is required for recognition of all BMPs, and targeted deletion of BMPRII in mice results in fetal lethality before gastrulation. To overcome this limitation and study the role of BMP signaling in postnatal vascular disease, we constructed a smooth muscle-specific transgenic mouse expressing a dominant-negative BMPRII under control of the tetracycline gene switch (SM22-tet-BMPRIIdelx4+ mice). When the mutation was activated after birth, mice developed increased pulmonary artery pressure, RV/LV+S ratio, and pulmonary arterial muscularization with no increase in systemic arterial pressure. Studies with SM22-tet-BMPRIIdelx4+ mice support the hypothesis that loss of BMPRII signaling in smooth muscle is sufficient to produce the pulmonary hypertensive phenotype.
Key words: artery • bone morphogenetic peptide • hypertension • smooth muscle • vascular
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