Estradiol, acting through ERα, induces endothelial non-classic renin-angiotensin system increasing angiotensin 1-7 production

Mol Cell Endocrinol. 2016 Feb 15;422:1-8. doi: 10.1016/j.mce.2015.11.004. Epub 2015 Nov 11.


Intracellular renin-angiotensin system (RAS) can operate independently of the circulating RAS. Estrogens provide protective effects by modulating the RAS. Our aim was to investigate the effect of estradiol (E2) on angiotensin converting enzymes (ACE) 1 and ACE2 expression and activities in human endothelial cells (HUVEC), and the role of estrogen receptors (ER). The results confirmed the presence of active intracellular RAS in HUVEC. Physiological concentrations of E2 induced a concentration-dependent increase of ACE1 and ACE2 mRNA expression and ACE1, but not ACE2, protein levels. ACE1 and ACE2 enzymatic activities were also induced with E2. These effects were mediated through ERα activation, since ER antagonists ICI 182780 and MPP completely abolished the effect of E2. Moreover, the ERα agonist PPT mirrored the E2 effects on ACE1 and ACE2 protein expression and activity. Exposure of endothelial cells to E2 significantly increased Ang-(1-7) production. In conclusion, E2 increases Ang-(1-7) production, through ERα, involving increased ACE1 and ACE2 mRNA expression and activity and ACE1 protein levels.

Keywords: Angiotensin converting enzymes; Endothelial cell; Estrogen; Estrogen receptor; Renin angiotensin system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / metabolism*
  • Angiotensin-Converting Enzyme 2
  • Dose-Response Relationship, Drug
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology*
  • Estrogen Receptor Antagonists / pharmacology
  • Estrogen Receptor alpha / metabolism*
  • Fulvestrant
  • Gene Expression Regulation / drug effects
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Peptide Fragments / metabolism*
  • Peptidyl-Dipeptidase A / genetics*
  • Peptidyl-Dipeptidase A / metabolism
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology


  • 1,3-bis(4-hydroxyphenyl)-4-methyl-5-(4-(2-piperidinylethoxy)phenol)-1H-pyrazole
  • ESR1 protein, human
  • Estrogen Receptor Antagonists
  • Estrogen Receptor alpha
  • Peptide Fragments
  • Piperidines
  • Pyrazoles
  • Fulvestrant
  • Estradiol
  • Angiotensin I
  • ACE protein, human
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • angiotensin I (1-7)