| First Author | de Jesus Perez VA | Year | 2012 |
| Journal | Circ Res | Volume | 111 |
| Issue | 12 | Pages | 1551-64 |
| PubMed ID | 23011394 | Mgi Jnum | J:212880 |
| Mgi Id | MGI:5582381 | Doi | 10.1161/CIRCRESAHA.112.267849 |
| Citation | de Jesus Perez VA, et al. (2012) Loss of adenomatous poliposis coli-alpha3 integrin interaction promotes endothelial apoptosis in mice and humans. Circ Res 111(12):1551-64 |
| abstractText | RATIONALE: Pulmonary hypertension (PH) is characterized by progressive elevation in pulmonary pressure and loss of small pulmonary arteries. As bone morphogenetic proteins promote pulmonary angiogenesis by recruiting the Wnt/beta-catenin pathway, we proposed that beta-catenin activation could reduce loss and induce regeneration of small pulmonary arteries (PAs) and attenuate PH. OBJECTIVE: This study aims to establish the role of beta-catenin in protecting the pulmonary endothelium and stimulating compensatory angiogenesis after injury. METHODS AND RESULTS: To assess the impact of beta-catenin activation on chronic hypoxia-induced PH, we used the adenomatous polyposis coli (Apc(Min/+)) mouse, where reduced APC causes constitutive beta-catenin elevation. Surprisingly, hypoxic Apc(Min/+) mice displayed greater PH and small PA loss compared with control C57Bl6J littermates. PA endothelial cells isolated from Apc(Min/+) 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 alpha3 integrin, to stabilize focal adhesions and activate integrin-linked kinase-1 and phospho Akt. We found that PA endothelial cells 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 PA endothelial cells adhesion and survival and is reduced in PA endothelial cells 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. |
