This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. One of the signaling systems critical in protection against the development of pulmonary hypertension is that through the bone morphogenetic protein receptor 2 (BMPRII). Mutations that lead to loss of signaling through BMPRII receptors are found in 70% of cases of familial pulmonary hypertension. Preliminary data from our lab has indicated that the multi-functional adapter protein beta-arrestin (1 and 2) binds and regulates signaling by BMPRII. To better understand the functional consequences of this altered signaling, we have subjected wild type, beta-arrestin1 and beta-arrestin2 KO animals to conditions of chronic hypoxia (simulated altitude) that lead to the development of pulmonary hypertension. In preliminary studies, we have demonstrated that beta-arrestin KO mice show altered susceptibility to the development of pulmonary hypertension induced by chronic hypoxia as assessed by differences in right ventricular hypertrophy (mass of RV / mass of LV + septum). We now plan on characterizing these differences better by more detailed analysis of cardiac and pulmonary morphology by microCT. We hope that studies by microCT will allow a detailed analysis of RV morphology, stroke volume (and cardiac output) and of changes in the pulmonary vasculature (loss of small vessels resulting in """"""""pruning""""""""). In concert with our preliminary data and data from cardiac catheterization, we will be able to comprehensively characterize changes in the development of pulmonary hypertension in the beta-arrestin KO mice and correlate this with changes in the BMPRII signaling.
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