Abstract Body: Abstract
Background: Fibrillin-1 (FBN1) is essential for the structural integrity of the aortic wall. Our recent study revealed that FBN1 deficiency in smooth muscle cells (SMCs) induces aortic aneurysms, predominantly affecting the distal portion of the ascending aorta and aortic arch. This study aimed to determine whether angiotensin II (AngII) augments aortic pathologies in mice with FBN1 deficiency in SMCs.
Methods: Male Sm22α-Cre^+/0;Fbn1 floxed mice were bred with female Sm22α-Cre^0/0; Fbn1 floxed mice to generate SMC-FBN1-deficient mice (SMC-FBN1 -/-: Sm22α-Cre^+/0; Fbn1^fl/fl) and their wild-type littermates (SMC-FBN1 +/+: Sm22α-Cre^0/0;Fbn1^fl/fl). Vehicle (saline) or AngII (1 or 0.5 µg/kg/min) was infused into 7-8-week-old mice for 28 days. At study termination, micro-computed tomography was used to visualize aortic pathologies and quantify aortic diameters, lengths, and volumes. Both male and female mice were studied.
Results: Infusion of AngII at a rate of 1 µg/kg/min resulted in >70% death due to aortic rupture in either the thoracic or abdominal region of SMC-FBN1 -/- mice of both sexes. Infusion at 0.5 µg/kg/min led to mortality rates of 27% in males and 50% in females. In addition to pathologies in the ascending aorta and aortic arch, prominent pathological features were observed in surviving AngII-infused SMC-FBN1 -/- mice, including: (1) increased total aortic length; (2) pronounced pathological changes in the descending and suprarenal aortic regions, with the infrarenal aorta relatively spared; (3) branch aneurysms involving the celiac and superior mesenteric arteries; and (4) cardiac enlargement, including enlarged hearts or left atria, observed in approximately 64% of males and 25% of females.
Conclusions: AngII infusion exacerbates aortic pathology in SMC-FBN1 -/- mice, manifested by aortic rupture, increased aortic tortuosity, widespread aortic aneurysms, aneurysms of the celiac and superior mesenteric arteries, and cardiac enlargement.
Keywords: smooth muscle cell; FBN1; extracellular matrix; aortopathy; AngII; mouse