Abstract 207: Angiotensin 1-7 Reduces Mortality and Aneurysm Rupture in a Mouse Model of Intracranial Aneurysms

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Abstract

Inflammation has been linked to progression and rupture of intracranial aneurysms in humans and animal models. Angiotensin II drives vascular inflammation in several models of vascular disease. Angiotensin 1-7, the product of metabolism of angiotensin II by ACE2, acts on Mas receptors and counteracts the deleterious effects of angiotensin II. We previously demonstrated that ACE2 deficiency is associated with cerebrovascular dysfunction. We now explore the hypothesis that angiotensin 1-7 attenuates formation and rupture of intracranial aneurysms in mice. In wild type (WT) C57Bl/6 mice an intracranial injection of elastase was made, and then angiotensin II (Ang II) or angiotensin II + angiotensin 1-7 (Ang II + Ang 1-7) were infused for 3 weeks. Increase in systolic pressure was similar in mice receiving Ang II (146±5 mmHg, mean ±SE) or Ang II + Ang 1-7 (147±5 mmHg). Mortality was higher in Ang II-treated mice (64% (16/25)) than in Ang II + Ang 1-7-infused mice (33% (7/21) p<0.05). Aneurysm formation was similar in both groups (88% (22/25) Ang II vs. 81% (17/21) Ang II + ang 1-7). Incidence of subarachnoid hemorrhage (SAH) was lower (43% (9/21)) in Ang II + Ang 1-7 than in Ang II treated mice (68% (17/25), p<0.05). Similar studies were performed in Mas receptor knockout mice (Mas-KO). Increase in systolic pressure was similar (136±4 vs. 137±8 mmHg) in Mas-KO mice that received Ang II or Ang II + Ang 1-7 respectively. There was no significant difference in aneurysm formation (83% 10/12 vs. 100% 14/14) or SAH incidence (50% 6/12 vs. 64% 9/14) in Mas-KO mice treated with Ang II or Ang II + Ang 1-7 respectively (p>0.05). In conclusion, angiotensin 1-7 does not attenuate the increase in systolic blood pressure induced by Ang II in WT or Mas-KO mice. Angiotensin 1-7 does not affect the incidence of aneurysm formation in this mouse model of intracranial aneurysms. Importantly, angiotensin 1-7 decreases mortality and intracranial aneurysm rupture. Protective effects of angiotensin 1-7 on aneurysm rupture are not seen in Mas-KO mice, confirming that these effects of angiotensin 1-7 are mediated by its receptor Mas. We speculate that angiotensin 1-7 may be of therapeutic value for prevention of rupture of intracranial aneurysms.

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