title: S-endoglin expression is induced in senescent endothelial cells and contributes to vascular pathology.
abstract: 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)-beta 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-beta receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-beta 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-beta-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-beta(1) 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.
authors.affiliation: Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Blanco
authors.forename: María T
authors.initials: MT
authors.lastname: Grande
authors.forename: Carmen
authors.initials: C
authors.lastname: Langa
authors.forename: Barbara
authors.initials: B
authors.lastname: Oujo
authors.forename: Soraya
authors.initials: S
authors.lastname: Velasco
authors.forename: Alicia
authors.initials: A
authors.lastname: Rodriguez-Barbero
authors.forename: Eduardo
authors.initials: E
authors.lastname: Perez-Gomez
authors.forename: Miguel
authors.initials: M
authors.lastname: Quintanilla
authors.forename: Jose M
authors.initials: JM
authors.lastname: López-Novoa
authors.forename: Carmelo
authors.initials: C
authors.lastname: Bernabeu
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D019556:COS Cells; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D002522:Chlorocebus aethiops; D000071063:Endoglin; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000473:pathology* / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D014652:Vascular Diseases / Q000097:blood / Q000235:genetics / Q000473:pathology
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D020033:Protein Isoforms; D011956:Receptors, Cell Surface