Biochemical, genetic, and clinical evidence indicates that smooth muscle cell proliferation around small pulmonary vessels is an essential part of the pathogenesis of pulmonary hypertension. We have shown that Angiopoietin- 1 (Ang-1), a smooth muscle cell mitogen in embryogenesis is overexpressed in the lungs of patients with pulmonary hypertension and is not detectable in normal human lung tissue. Indeed, Ang-1 protein and the degree of phosphorylation of its endothelial-specific receptor TIE2 are sensitive molecular markers for the severity of pulmonary hypertension in different forms of this disease. Building on this result, we have created an animal model for pulmonary hypertension by injecting an adenovirus containing the Ang-1 gene into the pulmonary vasculature of the rat and have shown that targeted overexpression of Ang-1 induces this disease. We have subsequently shown that Ang-1 stimulated pulmonary artery endothelial cells release a factor(s) that stimulates smooth muscle cell proliferation in culture. ? ? Recently, we have linked the genetic mechanism of familial and sporadic pulmonary hypertension by showing that Ang-1 downregulates the expression of Bone Morphogenetic Protein Receptor Type 1 (BMPR1) in pulmonary endothelial cells. BMPR1 is known to complex with BMPR2 on the cell surface, leading to activation of BMPR1 as a serine/threonine kinase capable of initiating intracellular signaling via Smad-related pathways. Given that BMPR2 mutation is associated with human familial pulmonary hypertension, and that in order for the BMPRS to transduce intracellular signals, BMPR1 and 2 must associate on the cell surface, we hypothesize that nonfamilial forms of this disease occur through an Ang-1/TIE2/BMPR1 cascade. ? ? We propose to extend these findings in order to solidify and clarify the role of Ang-1, TIE2, and BMPR1 in pulmonary hypertension. To this end, we will: 1) investigate how Ang-1 causes pulmonary hypertension in an in vivo model and, in specific, determine if disruption of the Ang-1/TIE2 signaling pathway in the lung will attenuate or arrest the disease process, 2) characterize the promoter/repressor sequences in BMPR1 which govern its expression in pulmonary endothelial cells and understand the mechanism of how BMPR1 is shut off at the mRNA level by TIE2 signaling in pulmonary hypertension. and 3) identify the specific secreted factor(s) made by Ang-1 activated endothelial cells that trigger vascular smooth muscle proliferation. Information gained from these proposed experiments should elucidate a molecular mechanism for pulmonary hypertension and suggest possible treatment strategies for this disease.
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