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Endothelial-specific expression of CIDEC improves high-fat diet-induced vascular and metabolic dysfunction

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posted on 2022-10-18, 18:05 authored by Bijinu Balakrishnan, Abhishek Gupta, Rabia Basri, Vishva M. Sharma, Mark Slayton, Kailey Gentner, Chloe C. Becker, Shakun Karki, Harrison Muturi, Sonia M. Najjar, Analia S. Loria, Noyan Gokce, Vishwajeet Puri

  

Cell death-inducing DNA fragmentation factor-α-like effector C (CIDEC), originally identified to be a lipid-droplet associated protein in adipocytes, positively associates with insulin sensitivity. Recently, we discovered that it is expressed abundantly in human endothelial cells (ECs) and regulates vascular function.  The present study was designed to characterize the physiological effects and molecular actions of endothelial CIDEC in the control of vascular phenotype and whole-body glucose homeostasis. To achieve this, we generated a humanized mouse model expressing endothelial-specific human CIDEC (E-CIDECtg). E-CIDECtg mice exhibited protection against HFD-impaired glucose intolerance, insulin resistance, and dyslipidemia. Moreover, these mice displayed improved insulin signaling and eNOS activation, enhanced endothelium-dependent vascular relaxation, and improved vascularization of adipose tissue, skeletal muscle, and heart.  Mechanistically, we identified a novel interplay of CIDEC-VEGFA-VEGFR2 that reduced VEGFA and VEGFR2 degradation thereby increasing VEGFR2 activation. Overall, our results demonstrate a protective role of endothelial CIDEC against obesity-induced metabolic and vascular dysfunction, in part, by modulation of VEGF signaling. These data suggest that CIDEC may be investigated as a potential future therapeutic target for mitigating obesity-related cardiometabolic disease.

Funding

This work was supported by NIH grant R01DK101711 (VP), R01HL140836 (NG and VP), R01HL142650 (NG), R01DK124126 (SN and VP), funds from Osteopathic Heritage Foundation’s Vision 2020 to Heritage College of Osteopathic Medicine at Ohio University (VP), and American Heart Association Postdoctoral Fellowship grant 19POST34430086 (BB).

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