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

BACKGROUND: Mice harboring a missense variant (C1041G) of Fbn1 have been used extensively for aortopathy research, but do not mimic all facets of the human disease. The role of increased AngII (angiotensin II) or blood pressure in determining the arterial phenotype of these mice remains incompletely defined. The purpose of this study was to determine whether AngII, either directly or indirectly through increased blood pressure, promotes pathology in the proximal thoracic aorta and beyond. METHODS: Fbn1 +/+ and Fbn1 C1041G/+ littermates were infused with either AngII or norepinephrine via subcutaneously implanted osmotic pumps. Microcomputed tomography was used to visualize vascular pathologies. Maximal arterial dimensions were measured using in situ or microcomputed tomography images. 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 increased ascending and suprarenal aortic diameters and developed pathological lesions at the celiac and superior mesenteric branches of the abdominal aorta. Female mice had a much lower incidence of death but had increased ascending aortic and branch diameters. Although norepinephrine infusion also increased systolic blood pressure, it did not affect mortality or enlarge aortic or branch diameters in Fbn1 C1041G/+ mice. Microcomputed tomography identified novel pathological changes during AngII infusion, including the development of aortic branch aneurysms in the celiac and superior mesenteric arteries; however, the maximal diameters of the adjacent suprarenal aorta showed only modest increases in male Fbn1 C1041G/+ mice. CONCLUSIONS: AngII exacerbated aortic pathology in Fbn1 C1041G/+ mice. It also promoted the development of pathologies at aortic branch points, including the celiac and superior mesenteric arteries.