Circ Res

Abstract

RationalePulmonary hypertension (PH) is characterized by progressive elevation in pulmonary pressure and loss of small pulmonary arteries. As bone morphogenetic proteins (BMPs) promote pulmonary angiogenesis by recruiting the Wnt/\u3b2catenin pathway, we proposed that \u3b2catenin activation could reduce loss and/or induce regeneration of small PAs and attenuate PH.ObjectiveThis study aims to establish the role of \u3b2\u2013catenin in protecting the pulmonary endothelium and stimulating compensatory angiogenesis following injury.Methods and ResultsTo assess the impact of \u3b2-catenin activation on chronic hypoxia-induced PH, we used the adenomatous polyposis coli (ApcMin/+) mouse, where reduced APC causes constitutive \u3b2\u2013catenin elevation. Surprisingly, hypoxic ApcMin/+ mice displayed greater PH and small PA loss compared to control C57Bl6J (C57) littermates. Pulmonary artery endothelial cells (PAECs) isolated from ApcMin/+ demonstrated reduced survival and angiogenic responses along with a profound reduction in adhesion to laminin. The mechanism involved failure of APC to interact with the cytoplasmic domain of the \u3b13 integrin, to stabilize focal adhesions and activate integrin-linked kinase (ILK-1) and pAkt. We found that PAECs from lungs of patients with idiopathic PH have reduced APC expression, decreased adhesion to laminin and impaired vascular tube formation. These defects were corrected in the cultured cells by transfection of APC.ConclusionsWe show that APC is integral to PAEC adhesion and survival and is reduced in PAECs from PH patient lungs. The data suggest that decreased APC may be a cause of increased risk or severity of PH in genetically susceptible individuals.R01 HL074186/HL/NHLBI NIH HHS/United StatesS10 RR027425/RR/NCRR NIH HHS/United StatesK12 RFA-HL-07-004:CDP/CD/ODCDC CDC HHS/United StatesS10RR027425/RR/NCRR NIH HHS/United States2013-12-07T00:00:00Z23011394PMC3821702vault:765