1. Endothelial deficiency of insulin-like growth factor-1 receptor reduces endothelial barrier function and promotes atherosclerosis in Apoe-deficient mice.
- Author
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Yusuke Higashi, Sukhanov, Sergiy, Shaw-Yung Shai, Danchuk, Svitlana, Snarski, Patricia, Zhaohui Li, Xuwei Hou, Hamblin, Milton H., Woods, T. Cooper, Meifang Wang, Derek Wang, Hong Yu, Korthuis, Ronald J., Tadashi Yoshida, and Delafontaine, Patrice
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ADHERENS junctions ,CELL junctions ,ATHEROSCLEROSIS ,APOLIPOPROTEIN E ,HIGH-fat diet ,CADHERINS - Abstract
First published August 14, 2020; doi:10.1152/ajpheart.00064.2020.--Insulin-like growth factor-1 (IGF-1) decreases atherosclerosis in apolipoprotein E (Apoe)-deficient mice when administered systemically. However, mechanisms for its atheroprotective effect are not fully understood. We generated endothelium-specific IGF-1 receptor (IGF1R)-deficient mice on an Apoe-deficient background to assess effects of IGF-1 on the endothelium in the context of hyperlipidemia-induced atherosclerosis. Endothelial deficiency of IGF1R promoted atherosclerotic burden, when animals were fed on a high-fat diet for 12 wk or normal chow for 12 mo. Under the normal chow feeding condition, the vascular relaxation response to acetylcholine was increased in the endothelial IGF1R-deficient aorta; however, feeding of a high-fat diet substantially attenuated the relaxation response, and there was no difference between endothelial IGF1R-deficient and control mice. The endothelium and its intercellular junctions provide a barrier function to the vasculature. In human aortic endothelial cells, IGF-1 upregulated occludin, claudin 5, VE-cadherin, JAM-A, and CD31 expression levels, and vice versa, specific IGF1R inhibitor, picropodophyllin, an IGF1R-neutralizing antibody (IR3), or siRNA to IGF1R abolished the IGF-1 effects on junction and adherens proteins, suggesting that IGF-1 promoted endothelial barrier function. Moreover, endothelial transwell permeability assays indicated that inhibition of IGF-1 signaling elevated solute permeability through the monolayer of human aortic endothelial cells. In summary, endothelial IGF1R deficiency increases atherosclerosis, and IGF-1 positively regulates tight junction protein and adherens junction protein levels and endothelial barrier function. Our findings suggest that the elevation of the endothelial junction protein level is, at least in part, the mechanism for antiatherogenic effects of IGF-1. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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