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Subsequently we demonstrated the functional relevance of this finding in arteries from mice with genetic, pharmacological, and age-associated EC autophagy impairment. Using gain and loss of function approaches in vitro, we further revealed that p-PKC\u03b4\n                    <jats:sup>T505<\/jats:sup>\n                    serves as a signaling link between P2Y1R activation and NO generation. Here we sought to discern the functional relevance of this observation. First, shear-stress- induced activating phosphorylation of eNOS (p-eNOS\n                    <jats:sup>S1177<\/jats:sup>\n                    ) that is otherwise prevented by knockdown of autophagy-related gene 3 (\n                    <jats:italic>Atg3<\/jats:italic>\n                    ) in ECs was restored by the PKC agonist bryostatin-1. Next, in murine models of genetic and age-associated EC autophagy compromise, depressed vasodilation displayed by femoral and cerebral arteries was reversed by bryostatin-1 in a manner that could be prevented by concurrent NO synthase inhibition. Finally, the bryostatin-1-mediated normalization of intraluminal flow-induced vasodilation observed in femoral arteries from both models of EC autophagy disruption was mitigated by inhibiting downstream targets of p-PKC\u03b4\n                    <jats:sup>T505<\/jats:sup>\n                    i.e., p-PKD\n                    <jats:sup>S744\/S748<\/jats:sup>\n                    and p-PKD\n                    <jats:sup>S916<\/jats:sup>\n                    . These findings provide evidence that stimulating PKC\/PKD has strategic potential to restore compromised endothelial function in pathologies associated with suppressed EC autophagy e.g., aging.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s11357-025-01650-5","type":"journal-article","created":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T02:39:26Z","timestamp":1744425566000},"page":"351-366","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Bryostatin-1 improves function in arteries with suppressed endothelial cell autophagy"],"prefix":"10.1007","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4461-6945","authenticated-orcid":false,"given":"Jae Min","family":"Cho","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seul-Ki","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sohom","family":"Mookherjee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily Carolyn","family":"Peters","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulo W.","family":"Pires","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2021-4770","authenticated-orcid":false,"given":"J. 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