Angiotensin-(1-7) protects against the development of aneurysmal subarachnoid hemorrhage in mice

J Cereb Blood Flow Metab. 2015 Jul;35(7):1163-8. doi: 10.1038/jcbfm.2015.30. Epub 2015 Mar 11.

Abstract

Angiotensin-(1-7) (Ang-(1-7)) can regulate vascular inflammation and remodeling, which are processes that have important roles in the pathophysiology of intracranial aneurysms. In this study, we assessed the effects of Ang-(1-7) in the development of intracranial aneurysm rupture using a mouse model of intracranial aneurysms in which aneurysmal rupture (i.e., aneurysmal subarachnoid hemorrhage) occurs spontaneously and causes neurologic symptoms. Treatment with Ang-(1-7) (0.5 mg/kg/day), Mas receptor antagonist (A779 0.5 mg/kg/day or 2.5 mg/kg/day), or angiotensin II type 2 receptor (AT2R) antagonist (PD 123319, 10 mg/kg/day) was started 6 days after aneurysm induction and continued for 2 weeks. Angiotensin-(1-7) significantly reduced the rupture rate of intracranial aneurysms without affecting the overall incidence of aneurysms. The protective effect of Ang-(1-7) was blocked by the AT2R antagonist, but not by the Mas receptor antagonist. In AT2R knockout mice, the protective effect of Ang-(1-7) was absent. While AT2R mRNA was abundantly expressed in the cerebral arteries and aneurysms, Mas receptor mRNA expression was very scarce in these tissues. Angiotensin-(1-7) reduced the expression of tumor necrosis factor-α and interleukin-1β in cerebral arteries. These findings indicate that Ang-(1-7) can protect against the development of aneurysmal rupture in an AT2R-dependent manner.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aneurysm, Ruptured / complications
  • Aneurysm, Ruptured / genetics
  • Aneurysm, Ruptured / pathology
  • Aneurysm, Ruptured / prevention & control*
  • Angiotensin I / therapeutic use*
  • Angiotensin II / analogs & derivatives
  • Angiotensin II / therapeutic use
  • Angiotensin II Type 2 Receptor Blockers / therapeutic use
  • Animals
  • Brain / blood supply*
  • Cerebral Arteries / drug effects
  • Cerebral Arteries / metabolism
  • Cerebral Arteries / pathology
  • Cytokines / analysis
  • Imidazoles / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peptide Fragments / therapeutic use*
  • Pyridines / therapeutic use
  • RNA, Messenger / genetics
  • Receptor, Angiotensin, Type 2 / genetics
  • Subarachnoid Hemorrhage / complications
  • Subarachnoid Hemorrhage / genetics
  • Subarachnoid Hemorrhage / pathology
  • Subarachnoid Hemorrhage / prevention & control*

Substances

  • 7-Ala-angiotensin (1-7)
  • Angiotensin II Type 2 Receptor Blockers
  • Cytokines
  • Imidazoles
  • Peptide Fragments
  • Pyridines
  • RNA, Messenger
  • Receptor, Angiotensin, Type 2
  • Angiotensin II
  • PD 123319
  • Angiotensin I
  • angiotensin I (1-7)