Bone morphogenic proteins have a well-described role in development, and targeted disruption of the pathway in mice results in fetal lethality prior to gastrulation. Thus, it was surprising when the gene responsible for the majority of cases of hereditary pulmonary arterial hypertension (PAH) was identified as the type II bone morphogenic protein receptor (BMPRII). We therefore constructed a conditional, smooth-muscle-specific transgenic mouse expressing a dominant-negative BMPRII mutation identified in a family with PAH (SM22-tet-dnBMPRII mice). We then addressed the following questions: (1) is loss of functional BMPRII in smooth muscle sufficient to produce the disease phenotype, and (2) despite generalized smooth-muscle expression of the mutant gene, are abnormalities restricted to the pulmonary circulation? Just as is seen in humans, SM22-tetdnBMPRII mice acquired severe PAH at sea level, associated with increased muscularization of small pulmonary arteries with no abnormality in systemic BP. Analysis of gene expression patterns by GeneChip (Affymetrix; Santa Clara, CA) showed a pattern of gene regulation markedly different from that in hypoxic pulmonary hypertension, including differential regulation of genes involved in cytoskeletal rearrangement, inflammation, and vascular tone. The mice were hyperresponsive to hypoxia, becoming even more severely hypertensive when kept at Denver altitude. In conclusion, we report the first transgenic model of PAH, establishing that selective smooth-muscle expression of a mutant BMPRII gene found in a family with PAH recapitulates the disease phenotype in transgenic mice.