期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 38, 期 3, 页码 588-591出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.117.310609
关键词
aneurysm; endothelial cells; fibrillin-1; homeostasis; Marfan syndrome
资金
- National Institutes of Health [AR069307]
- National Marfan Foundation
- Elster Family Research Endowment
Objective Two were the aims of this study: first, to translate whole-genome expression profiles into computational predictions of functional associations between signaling pathways that regulate aorta homeostasis and the activity of angiotensin II type 1a receptor (At1ar) in either vascular endothelial or smooth muscle cells; and second, to characterize the impact of endothelial cell- or smooth muscle cell-specific At1ar disruption on the development of thoracic aortic aneurysm in fibrillin-1 hypomorphic (Fbn1(mgR/mgR)) mice, a validated animal model of early onset progressively severe Marfan syndrome. Approach and ResultsCdh5-Cre and Sm22-Cre transgenic mice were used to inactivate the At1ar-coding gene (Agt1ar) in either intimal or medial cells of both wild type and Marfan syndrome mice, respectively. Computational analyses of differentially expressed genes predicted dysregulated signaling pathways of cell survival and matrix remodeling in Agt1ar(Cdh5-/-) aortas and of cell adhesion and contractility in Agt1ar(Sm22-/-) aortas. Characterization of Fbn1(mgR/mgR);Agt1ar(Cdh5-/-) mice revealed increased median survival associated with mitigated aneurysm growth and media degeneration, as well as reduced levels of phosphorylated (p-) Erk1/2 but not p-Smad2. By contrast, levels of both p-Erk1/2 and p-Smad2 proteins were normalized in Fbn1(mgR/mgR);Agt1ar(Sm22-/-) aortas in spite of them showing no appreciable changes in thoracic aortic aneurysm pathology. Conclusions Physiological At1ar signaling in the intimal and medial layers is associated with distinct regulatory processes of aorta homeostasis and function; improper At1ar activity in the vascular endothelium is a significant determinant of thoracic aortic aneurysm development in Marfan syndrome mice.
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