Vinicio de Jesus Perez MD

Publication Details

  • Loss of adenomatous poliposis coli-a3 integrin interaction promotes endothelial apoptosis in mice and humans. Circulation research de Jesus Perez, V. A., Yuan, K., Orcholski, M. E., Sawada, H., Zhao, M., Li, C. G., Tojais, N. F., Nickel, N., Rajagopalan, V., Spiekerkoetter, E., Wang, L., Dutta, R., Bernstein, D., Rabinovitch, M. 2012; 111 (12): 1551-1564

    Abstract:

    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/?-catenin pathway, we proposed that ?-catenin activation could reduce loss and induce regeneration of small pulmonary arteries (PAs) and attenuate PH.This study aims to establish the role of ?-catenin in protecting the pulmonary endothelium and stimulating compensatory angiogenesis after injury.To assess the impact of ?-catenin activation on chronic hypoxia-induced PH, we used the adenomatous polyposis coli (Apc(Min/+)) mouse, where reduced APC causes constitutive ?-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 ?3 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.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.

    View details for DOI 10.1161/CIRCRESAHA.112.267849

    View details for PubMedID 23011394

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