Angiotensin II Induces Abdominal Aortic Branch Aneurysms in Fibrillin-1 ^C1041G/+ Mice

Background

Mice harboring a missense variant (C1041G) of fibrillin-1 ( Fbn1 ) have been used extensively for aortopathy research, but do not mimic all facets of the human disease. The role of increased angiotensin II (AngII) or blood pressure in determining the arterial phenotype of these mice remains incompletely defined. The purpose of this study was to define whether AngII, directly or via increased blood pressure, promoted aortic disease in the proximal thoracic aorta and beyond.

Methods

Fbn1 ^+/+ and Fbn1 ^C1041G/+ littermates were infused with either AngII or norepinephrine (NE) via subcutaneously implanted osmotic pumps. Aortic dimensions were determined using in situ imaging. Micro Computed tomography (microCT) was used to determine the localization of aortic pathologies.

Results

AngII infusion dramatically augmented aortopathy in Fbn1 ^C1041G/+ mice. Aortic dissection was visible within 3 days of AngII infusion. Over 50% of male Fbn1 ^C1041G/+ mice died during AngII infusion, primarily due to aortic rupture in either the thoracic or abdominal regions. Surviving males had greatly increased ascending aortic diameters and the appearance of pathology at branches of the abdominal aorta. Female mice had a much lower incidence of death but had greatly increased aortic diameters. Although NE infusion also increased systolic blood pressure, it did not significantly augment mortality or aortic diameters. MicroCT discerned novel pathology during AngII infusion that included development of branch aneurysms in the celiac and superior mesenteric arteries.

Conclusion

AngII greatly enhanced aortic pathology in Fbn1 ^C1041G/+ mice, manifested by aortic rupture in both the thoracic and abdominal regions and development of pathologies at aortic branches of the celiac and superior mesenteric arteries.

HIGHLIGHTS

• Aortic branch aneurysms have recently been demonstrated to be prominent in Marfan patients but have not been reported in Marfan mouse models.

• Angiotensin II infusion into fibrillin-1 ^C1041G/+ mice promoted development of prominent aortic pathologies, including enhanced aneurysm and rupture in both the thoracic and abdominal regions.

• Angiotensin II infusion into fibrillin-1 ^C1041G/+ mice promoted development of pronounced aneurysms at the aortic branches of the celiac and superior mesenteric arteries.