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.
| Majka, Susan; Hagen, Moira; Blackwell, Thomas et al. (2011) Physiologic and molecular consequences of endothelial Bmpr2 mutation. Respir Res 12:84 |
| Crona, Daniel; Harral, Julie; Adnot, Serge et al. (2009) Gene expression in lungs of mice lacking the 5-hydroxytryptamine transporter gene. BMC Pulm Med 9:19 |
| West, James; Harral, Julie; Lane, Kirk et al. (2008) Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions. Am J Physiol Lung Cell Mol Physiol 295:L744-55 |
| Tada, Yuji; Laudi, Sven; Harral, Julie et al. (2008) Murine pulmonary response to chronic hypoxia is strain specific. Exp Lung Res 34:313-23 |
| Hagen, Moira; Fagan, Karen; Steudel, Wolfgang et al. (2007) Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am J Physiol Lung Cell Mol Physiol 292:L1473-9 |
| Tada, Yuji; Majka, Susan; Carr, Michelle et al. (2007) Molecular effects of loss of BMPR2 signaling in smooth muscle in a transgenic mouse model of PAH. Am J Physiol Lung Cell Mol Physiol 292:L1556-63 |
| Case, D; Irwin, D; Ivester, C et al. (2007) Mice deficient in galectin-1 exhibit attenuated physiological responses to chronic hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 292:L154-64 |
| Young, Katharine A; Ivester, Charles; West, James et al. (2006) BMP signaling controls PASMC KV channel expression in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 290:L841-8 |
| West, James; Fagan, Karen; Steudel, Wolfgang et al. (2004) Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle. Circ Res 94:1109-14 |
