Primary pulmonary hypertension (PPH) is a potentially lethal disorder characterized by pulmonary vasoconstriction and vascular remodeling involving abnormal proliferation of fibroblasts, smooth muscle and endothelial cells. In the year 2000, mutations in the type 2 bone morphogenic protein receptor (BMPR2) were identified as the genetic basis for familial PPH and about 30% of sporadic PPH. BMP signaling had not previously been connected to pulmonary hypertension, and the mechanistic linkage is unknown. We hypothesize that in normal individuals the BMP pathway acts to down-regulate both inflammatory cytokine-mediated positive feedback loops and vascular smooth muscle cell proliferation. Insufficient BMP pathway activity in individuals with BMPR2 mutations leads to insufficient damping of these auto-regulatory loops, resulting in the PPH phenotype. We provide preliminary evidence in cell culture systems supporting this hypothesis and have constructed a unique series of transgenic mice to further test the hypothesis. These mice express a human dominant-negative BMPR2 (dnBMPR2) using the tetracycline gene switch system, allowing both spatial and temporal control of expression. We have successfully bred smooth muscle cell and epithelial cell specific dnBMPR2 expressing mice, and are constructing endothelial cell specific mice at this time. Using our in vitro and transgenic models we will test the following three specific aims: 1: Test the hypothesis that the BMP pathway is a negative modulator of the cytokine interleukin-6 (IL-6) in PA SMC, leading to reduced IL-6-mediated signaling and proliferation. 2: Test the hypothesis that loss of PA SMC BMPR2 function in SM22-dnBMPR2 transgenic mice leads to an exaggerated pulmonary hypertensive response in vivo. 3: Test the hypothesis that loss of BMPR2 function in lung cell types other than SMC also contributes to the development of pulmonary hypertension. Upon completion of our studies, we will have tested the hypothesis that the link between BMP signaling and pulmonary hypertension involves both regulation of the critical cytokine, IL-6, as well as modulation of smooth muscle cell proliferation. We will have also tested the role of four pulmonary cell types, smooth muscle, endothelium, airway epithelium and macrophages in the link between BMPR2 and pulmonary hypertension.
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