Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle.
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-BMPRII(delx4+) 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-BMPRII(delx4+) mice support the hypothesis that loss of BMPRII signaling in smooth muscle is sufficient to produce the pulmonary hypertensive phenotype.
West
James
J
University of Colorado Health Sciences Center, Division of Pulmonary Sciences and Critical Care Medicine and Department of Anesthesia, Denver, Colo 80262, USA.
Fagan
Karen
K
Steudel
Wolfgang
W
Fouty
Brian
B
Lane
Kirk
K
Harral
Julie
J
Hoedt-Miller
Marloes
M
Tada
Yuji
Y
Ozimek
John
J
Tuder
Rubin
R
Rodman
David M
DM
D000818:Animals; D001794:Blood Pressure; D052006:Bone Morphogenetic Protein Receptors, Type II; D004318:Doxycycline / Q000494:pharmacology; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011651:Pulmonary Artery / Q000503:physiopathology / Q000648:ultrastructure; D014162:Transfection; D019076:Transgenes
D017346:Protein Serine-Threonine Kinases; C498218:BMPR2 protein, human; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II; D004318:Doxycycline