Angiotensin 1–7 Reduces Mortality and Rupture of Intracranial Aneurysms in Mice

Abstract

Angiotensin II (Ang-II) stimulates vascular inflammation, oxidative stress, and formation and rupture of intracranial aneurysms in mice. Because angiotensin 1-7 (Ang-1-7) acts on Mas receptors and generally counteracts deleterious effects of Ang-II, we tested the hypothesis that Ang-1-7 attenuates formation and rupture of intracranial aneurysms. Intracranial aneurysms were induced in wild type and Mas receptor deficient mice using a combination of Ang-II-induced hypertension and intracranial injection of elastase in the basal cistern. Mice received elastase+Ang-II alone, or a combination of elastase+Ang-II+Ang-1-7. Aneurysm formation, prevalence of subarachnoid hemorrhage, mortality, and expression of molecules involved in vascular injury were assessed. Systolic blood pressure was similar in mice receiving elastase+Ang-II (148±5 mmHg, mean ±SE) or elastase+Ang-II+Ang-1-7 (144±5 mmHg). Aneurysm formation was also similar in mice receiving elastase+Ang-II (89%) or elastase+Ang-II+Ang-1-7 (84%). However, in mice that received elastase and Ang II, Ang-1-7 reduced mortality (from 64 to 36%, p<0.05) and prevalence of subarachnoid hemorrhage (from 75 to 48%, p<0.05). In cerebral arteries, expression of the inflammatory markers, Nox2 and catalase increased similarly in elastase+Ang-II or elastase+Ang-II+Ang-1-7 groups. Ang-1-7 increased expression of cyclooxygenase-2, and decreased expression of metalloproteinase 9 induced by elastase+Ang-II (p<0.05). In Mas receptor deficient mice, systolic blood pressure, mortality, and prevalence of subarachnoid hemorrhage were similar (p>0.05) in groups treated with elastase+Ang-II or elastase+Ang-II+Ang-1-7. Expression of Mas receptor was detected by immunohistochemistry in samples of human intracranial arteries and aneurysms. In conclusion, without attenuating Ang-II-induced hypertension, Ang-1-7 decreased mortality and rupture of intracranial aneurysms in mice, through a Mas receptor-dependent pathway.

Myeloperoxidase Is Increased in Human Cerebral Aneurysms and Increases Formation and Rupture of Cerebral Aneurysms in Mice

“…14,15 Twelve each of MPO KO (C57Bl/6J genetic background) and control C57Bl/6J mice (Jackson Laboratories), 17–18 weeks of age, were implanted with an osmotic mini-pump for continuous delivery of angiotensin II (1000 ng/kg/min), and injected with 35 mU elastase (Sigma) into the right basal cistern. Systolic arterial pressure was monitored by tail cuff, and neurological function was assessed daily.…”

Novel Role for Endogenous Hepatocyte Growth Factor in the Pathogenesis of Intracranial Aneurysms

“…This is followed by monocyte infiltration, activation, and release of several proinflammatory molecules in arterial walls. 4, 26 A later final common pathway appears to involve the release of matrix metalloproteinases and apoptosis of cellular constituents of the vessel wall, leading to aneurysmal remodeling, progression and rupture. 2, 4, 27–29 …”

“…4, 8, 21 Briefly, under anesthesia a longitudinal incision was made in the scalp and a 1 mm hole was drilled in the skull. A stereotactic injection of elastase (35 mU in 2.5 μl) was subsequently performed using the following coordinates: 2.7 mm posterior to the bregma, 1 mm to the right of the midline, depth of 6.3 mm from the skull.…”

“…1, 2 Various constituents of the inflammatory response appear to be increased in intracranial aneurysms including cytokines, chemokines, growth factors, reactive oxygen species, leukocytes, matrix metalloproteinases, and vascular smooth muscle cells. 2–4 Therapies targeting the inflammatory cascade have also shown promising results in humans and experimental animals. 2, 5–8 …”

Stages in Discovery

“…Angiotensin 1–7 also appears to play an important role in cerebrovascular disease. In stroke prone hypertensive rats 9 and in a mouse model of rupture of intracranial aneurysms 10 , angiotensin 1–7 appears to increase survival. The ACE2 /angiotensin 1–7/mas receptor axis also appears to be modulated and be beneficial in models of ischemic stroke.…”