Arterial dysfunction displayed by old mice with repressed endothelial cell autophagy is rescued by pharmacological activation of purinergic 2Y1 receptors

Abstract

Earlier we reported that genetic repression of endothelial cell (EC) autophagy impairs autocrine signaling via the purinergic 2Y1 (P2Y1) receptor to EC nitric oxide (NO) synthase (eNOS), and prevents NO generation in response to shear stress. Herein we sought to determine whether aging‐associated endothelial dysfunction displayed by mice with defective vascular autophagy could be restored by promoting purinergic signaling. First, mRNA and protein expression of autophagy markers was lower in ECs and arterial homogenates of 22–23 month old (old) vs. 6–7 month old (adult) mice. Second, the ability of aged mice with repressed basal autophagy to upregulate this process in response to physiological stimuli was prevented. Specifically, 14 h fasting and 60‐min treadmill‐running increased autophagy in arteries from adult but not old mice. Third, autophagy suppression (3‐methyladenine) impaired flow‐mediated vasodilation in arteries from adult mice evaluated ex vivo, while autophagy activation (trichostatin‐A) preserved vasodilation in arteries from older animals. Finally, the selective P2Y1 receptor agonist 2‐methylthio‐ADP restored arterial function in arteries from aged mice whereas P2Y1 receptor inhibition using MRS2179 precipitated an aging phenotype in vessels from adult animals. We provide the first evidence that aging : (i) prevents the autophagic response to fasting and acute exercise and (ii) attenuates flow‐mediated vasodilation in a manner that can be restored by intervening distal to defective vascular autophagy i.e., by pharmacological promotion of purinergic autocrine signaling. Further research concerning the G protein‐coupled P2Y family of receptors is warranted in an effort to explore new therapeutic treatment options for aging‐related endothelial dysfunction that is secondary to defective EC autophagy.Support or Funding InformationAHA 16GRNT31050004, NIH RO3AGO52848, Seed Grants from the UU Office of the Vice‐President for Research, the UU College of Health, the UU Center on Aging, the UU Diabetes and Metabolism Center, and the Diabetes Research Center at Washington University at Saint Louis 5 P30 DK020579 (JDS)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.