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Over-activity of the classic renin angiotensin system (RAS) has been implicated in the pathophysiology of cardiovascular diseases primarily through the vasoconstrictor and inflammatory properties of Angiotensin (Ang)II. The non-classic RAS may counteract some AngII effects through its diversion to synthesize the vasodilator Ang-(1-7). Wealth of evidence shows that estrogens provide vascular protective effects by modulating the RAS. We previously reported estradiol (E2) effects on endothelial gene expression profile, demonstrating an increase in ACE1. Our aims were to analyze the E2 effect on ACE1 and ACE2 expression and activities in human umbilical vein endothelial cells (HUVEC) and the role of estrogen receptors (ER).

Design and method:

Primary HUVEC were exposed to physiological concentrations (1–10 nM) of E2 for 24 hours. Cells were also exposed to specific agonists of ERalpha (PPT) and ERbeta (DPN) and to antagonists of ER (unspecific, ICI 182780, and selective for ERalpha, MPP) or to lisinopril (ACE1 inhibitor) to analyze their role on the observed effects. ACE1 and ACE2 expressions were analyzed by RT-PCR and immunoblotting. Their enzymatic activities were measured by fluorometry by using specific substrates. AngII and Ang-(1-7) production was detected by immunofluorescence.


HUVEC exposure to E2 resulted in a dose-dependent increase of both ACE1 and ACE2 mRNA expression. This ACE1 increment was confirmed with the amount of protein, while ACE2 protein expression remained unaltered. ACE1 and ACE2 enzymatic activities were also increased with E2. These effects were mediated through ERalpha activation, since ICI 182780 and MPP completely abolished the E2 effect. Exposure of HUVEC to E2 significantly increased Ang-(1-7) production. Treatment with MPP and lisinopril reverted the E2 mediated effects.


E2 increases Ang-(1-7) endothelial production by enhancing its local enzymatic regulation through ERalpha. Thus, our results add new information that supports a role for ERalpha in E2-mediated vasodilatory effects.


Supported by the Spanish Ministerio de Economía y Competitividad, ISCIII – FEDER-ERDF (grants FIS PI13/00091, PI13/00617, and RD12/0042/0052). D.P-C. is an ‘Atracció de Talent’ fellow (PREDOC13-110541, Univ. Valencia). A.M. is a ‘Formación de Profesorado Universitario’ fellow (FPU13/02235 Spanish Min. Educación, Cultura y Deporte).

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