Loss of Adenomatous Poliposis Coli-α3 Integrin Interaction Promotes Endothelial Apoptosis in Mice and Humans
Rationale: Pulmonary 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/β-catenin pathway, we proposed that βcatenin activation could reduce loss and/or induce regeneration of small PAs and attenuate PH.
Objective: This study aims to establish the role of β-catenin in protecting the pulmonary endothelium and stimulating compensatory angiogenesis following injury.
Methods and Results: To assess the impact of β-catenin activation on chronic hypoxia-induced PH, we used the adenomatous polyposis coli (ApcMin/+) mouse, where reduced APC causes constitutive β-catenin 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 α3 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.
Conclusions: We 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.
- Received February 23, 2012.
- Accepted September 25, 2012.
- Copyright © 2012, American Heart Association