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(Circulation Research. 2008;103:1383.)
© 2008 American Heart Association, Inc.

Molecular Medicine

S-Endoglin Expression Is Induced in Senescent Endothelial Cells and Contributes to Vascular Pathology

Francisco J. Blanco, María T. Grande, Carmen Langa, Barbara Oujo, Soraya Velasco, Alicia Rodriguez-Barbero, Eduardo Perez-Gomez, Miguel Quintanilla, Jose M. López-Novoa, Carmelo Bernabeu

From the Centro de Investigaciones Biologicas (F.J.B., C.L., C.B.), Consejo Superior de Investigaciones Cientificas, Madrid; CIBER de Enfermedades Raras (F.J.B., C.L., C.B.), Instituto de Salud Carlos III, Madrid; Instituto "Reina Sofía" de Investigación Nefrológica (M.T.G., B.O., S.V., A.R.-B, J.M.L.-N.), Departamento de Fisiologia & Farmacologia, Universidad de Salamanca and Red de Investigacion Renal; and Instituto de Investigaciones Biomedicas Alberto Sols (M.Q., E.P-G.), Consejo Superior de Investigaciones Cientificas–Universidad Autonoma de Madrid, Spain.

Correspondence to Carmelo Bernabeu, Centro de Investigaciones Biologicas, CSIC, Ramiro de Maetzu 9, 28040 Madrid, Spain. E-mail bernabeu.c{at}cib.csic.es

Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-β receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-β receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-β type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-β–responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-β₁ administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology.

Key Words: endothelial cells • hypertension • TGF-β receptors • aging • endoglin