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Earlier, we reported that intact EC autophagy is requisite to maintain shear-stress-induced nitric oxide (NO) generation via glycolysis-dependent purinergic signalling to endothelial NO synthase (eNOS). Here, we illustrate the translational and functional significance of these findings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>First, we assessed translational relevance using older male humans and mice that exhibit blunted EC autophagy and impaired arterial function vs. adult controls. Active hyperaemia evoked by rhythmic handgrip exercise-elevated radial artery shear-rate similarly from baseline in adult and older subjects for 60 min. Compared with baseline, indexes of autophagy initiation, p-eNOSS1177 activation, and NO generation, occurred in radial artery ECs obtained from adult but not older volunteers. Regarding mice, indexes of autophagy and p-eNOSS1177 activation were robust in ECs from adult but not older animals that completed 60-min treadmill-running. Furthermore, 20 dyne \u2022 cm2 laminar shear stress \u00d7 45-min increased autophagic flux, glycolysis, ATP production, and p-eNOSS1177 in primary arterial ECs obtained from adult but not older mice. Concerning functional relevance, we next questioned whether the inability to initiate EC autophagy, glycolysis, and p-eNOSS1177 \u00a0in vitro precipitates arterial dysfunction ex vivo. Compromised intraluminal flow-mediated vasodilation displayed by arteries from older vs. adult mice was recapitulated in vessels from adult mice by (i) NO synthase inhibition; (ii) acute autophagy impairment using 3-methyladenine (3-MA); (iii) EC Atg3 depletion (iecAtg3KO mice); (iv) purinergic 2Y1-receptor (P2Y1-R) blockade; and (v) germline depletion of P2Y1-Rs. Importantly, P2Y1-R activation using 2-methylthio-ADP (2-Me-ADP) improved vasodilatory capacity in arteries from (i) adult mice treated with 3-MA; (ii) adult iecAtg3KO mice; and (iii) older animals with repressed EC autophagy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Arterial dysfunction concurrent with pharmacological, genetic, and age-associated EC autophagy compromise is improved by activating P2Y1-Rs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvac061","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T05:48:26Z","timestamp":1649915306000},"page":"252-267","source":"Crossref","is-referenced-by-count":23,"title":["Activating P2Y1 receptors improves function in arteries with repressed autophagy"],"prefix":"10.1093","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4461-6945","authenticated-orcid":false,"given":"Jae Min","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Nutrition and Integrative Physiology, University of Utah , Salt Lake City, UT , USA"},{"name":"Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine University of Utah School of Medicine , Salt Lake City, UT , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7027-7679","authenticated-orcid":false,"given":"Seul-Ki","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Integrative Physiology, University of Utah , Salt Lake City, UT , USA"},{"name":"Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine University of Utah School of Medicine , Salt Lake City, UT , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9929-6774","authenticated-orcid":false,"given":"Oh Sung","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, University of Connecticut , Storrs, CT , USA"},{"name":"Department of Orthopedic Surgery & Center on Aging, University of Connecticut School of Medicine , Storrs, CT , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Taylor La Salle","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Integrative Physiology, University of Utah , Salt Lake City, UT , USA"},{"name":"Geriatric Research, Education, and Clinical Center, George E. Whalen Veterans Affairs Medical Center , Salt Lake City, UT , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Cerbie","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Integrative Physiology, University of Utah , Salt Lake City, UT , USA"},{"name":"Geriatric Research, Education, and Clinical Center, George E. Whalen Veterans Affairs Medical Center , Salt Lake City, UT , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1027-7081","authenticated-orcid":false,"given":"Caitlin C","family":"Fermoyle","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Integrative Physiology, University of Utah , Salt Lake City, UT , USA"},{"name":"Geriatric Research, Education, and Clinical Center, George E. Whalen Veterans Affairs Medical Center , Salt Lake City, UT , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0329-2523","authenticated-orcid":false,"given":"David","family":"Morgan","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Utah , Salt Lake City, UT , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley","family":"Nelson","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education, and Clinical Center, George E. 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Whalen Veterans Affairs Medical Center , Salt Lake City, UT , USA"},{"name":"Department of Internal Medicine, Division of Geriatrics, University of Utah , Salt Lake City, UT , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8424-5421","authenticated-orcid":false,"given":"Pon Velayutham","family":"Anandh Babu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Integrative Physiology, University of Utah , Salt Lake City, UT , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sohom","family":"Mookherjee","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Integrative Physiology, University of Utah , Salt Lake City, UT , USA"},{"name":"Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine University of Utah School of Medicine , Salt Lake City, UT , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bellamkonda K","family":"Kishore","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Integrative Physiology, University of Utah , Salt Lake City, UT , USA"},{"name":"Nephrology Research, George E. 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