The long-term goal of the proposal is to elucidate the role of transforming growth factor b family signals in the pathogenesis of 2 vascular diseases; hereditary hemorrhagic telangiectasia (HHT) and primary pulmonary hypertension (PPH). HHT is an autosomal dominant vascular disorder characterized by epistaxis, mucocutaneous telangiectases and arteriovenous malformations (AVM). Direct shunting of blood through cerebral AVMs may result in ischemic and/or hemorrhagic infarctions in the brain and lead to stroke. It has been shown that the reduced expression of either endoglin (ENG) or activin receptor-like kinase 1 (ALK1) causes HHT. Both genes are involved in the transforming growth factor b signaling pathways. However, the precise role of these genes in the pathogenesis of HHT remains elusive. PPH is a rare lung disorder (2-3 per million per year), in which the pulmonary artery pressure rises far above normal levels (25 mmHg at rest and 30mmHg during exercise) without an apparent reason. PPH is a fatal disease with mean survival from diagnosis of 2.8 years without proper treatment. Familial form of PPH are inherited in an autosomal dominant manner, and heterozygous mutations of bone morphogenic protein type II receptor (BMPR2) were found in a half of familial PPH cases. Furthermore, 26% of apparently sporadic PPH cases also contain germline BMPR2 mutations. In addition to BMPR2, recent studies have shown that HHT patients with ALK1 mutations also develop PPH. However, cellular and pathogenetic mechanisms underlying PPH have yet to be elucidated. Identification of signaling pathway of ALK1 is fundamental in understanding the pathogenic mechanism of HHT and PPH. We have previously hypothesized that both ALK1 and ALK5 (Tgfbrl) are type I receptor for TGF-B signal in endothelial cells, and TGF-B signal mediated by each type I receptor form an opposing balance which controls the property of endothelial cells during angiogenesis. This hypothesis was challenged by several other groups, and became evolved into a more complicated form. The immediate goals of this proposal are to dissolve the intertwined signaling mechanisms surrounding ALK1 in endothelium, and to develop animal models for PPH. Results from the proposed studies would provide novel insights and perspectives on the role of TGF-B signaling on endothelial functions and smooth muscle cell growth and differentiation, and also shed light on the understanding the pathologic mechanisms underlying HHT, PPH, atherosclerosis, and restenosis.
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