Abstract 132: Roles of Angiotensin (1-7) And Angiotensin II Type 2 Receptor on Intracranial Aneurysmal Rupture

Abstract

Background and Purpose: Angiotensin (Ang) 1-7 is emerging as a new key player of the vascular renin-angiotensin system. Ang (1-7) generated from either Ang I or Ang II, acts to oppose the vasoconstrictor and proinflammatory actions of Ang II. However, which receptor Ang (1-7) activates still remains unclear. It has been suggested that Ang (1-7) mediates its effect via Mas receptor (MasR), although some suggest that it may also act at Ang II type 2 receptor (AT2R). Therefore, we hypothesized that Ang (1-7) has protective effect against aneurysmal rupture via MasR or AT2R. We tested this hypothesis by using our own established mouse model of intracranial aneurysm. Methods: Intracranial aneurysms were induced in male mice using a combination of a single injection of elastase into the cerebrospinal fluid and the deoxycorticosterone acetate (DOCA) salt hypertension (Figure 1). Six days after aneurysm induction, we started 2-week treatment with vehicle or Ang (1-7). MasR antagonist (A779) or AT2R antagonist (PD123319) was added to Ang (1-7) treatment. We induced aneurysms to AT2R knockout mice and treated them with vehicle or Ang (1-7) with the same protocol mentioned above. Aneurysmal rupture was detected by neurological symptoms and confirmed by the presence of intracranial aneurysms with subarachnoid hemorrhage. Results: Ang (1-7) reduced the incidence of ruptured aneurysms and rupture rate. AT2R antagonist but not MasR antagonist reversed the reduced rupture rate by Ang (1-7) (Figure 2, 3). To confirm whether the effect of Ang (1-7) is through the AT2R, we administered Ang (1-7) to AT2R knockout mice. Although there was no significant difference between wild type and AT2R knockout mice, Ang (1-7) was not effective against aneurysmal rupture in AT2R knockout mice (Figure 4, 5). Conclusion: Our results indicate that Ang (1-7) is protective against intracranial aneurysmal rupture and that its protective effect is exerted via AT2R rather than MasR.