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We recently found that Cell death-inducing DNA fragmentation factor-a–like effector C (CIDEC), originally identified as lipid droplet-associated protein in adipocytes, is abundantly expressed in endothelial cells. We described its novel role in regulating vascular function in humans. To study the effect of endothelial-specific CIDEC in whole-body physiology and its molecular action in regulating vascular function, we generated a humanized mice model expressing endothelial-specific human CIDEC transgene (E-CIDECtg). E-CIDECtg mice showed protection against HFD-induced glucose intolerance and dyslipidemia. We also identified a molecular pathway of action whereby CIDEC directly regulates the VEGFA-VEGFR2 axis promoting eNOS signaling, angiogenesis, and vasodilation to improve metabolic health. Since aging and age-related declines in physical activity are associated with physical and metabolic impairment, and skeletal muscle capillarization is reduced in older adults, the objective of the present study was to evaluate the role of endothelial-specific CIDEC in the regulation of microvasculature remodeling in muscle, as well as muscle performance with aging. One-year to 14 months old E-CIDECtg mice (around 60 yrs human age) and their littermate controls were tested for muscle endurance and capillary density in the skeletal muscle. E-CIDECtg mice displayed enhanced muscle performance and higher capillary density in the skeletal muscle. Serum lipid parameters, LDL, triglycerides, fatty acids, and total cholesterol were lower, and the metabolic parameters including respiratory exchange ratio (muscle’s oxidative capacity), insulin tolerance and glucose tolerance were higher in aged E-CIDECtg mice. Overall, our study highlights endothelial-specific role of CIDEC in improving age-related decline in capillary density, muscle performance, and metabolic health. R01HL140836 and funds from Osteopathic Heritage Foundation's Vision 2020 to Heritage College of Osteopathic Medicine at Ohio University This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.