{"doi":"10.1007/s11357-025-01650-5","title":"Bryostatin-1 improves function in arteries with suppressed endothelial cell autophagy","abstract":"Abstract We have previously reported that when autophagy is suppressed in endothelial cells (ECs), a glycolytic defect limits shear-stress -induced ATP production to an extent that purinergic 2Y1 receptor (P2Y1R)-mediated activation of EC nitric oxide (NO) synthase (eNOS) is compromised. 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-PKCδ T505 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 S1177 ) that is otherwise prevented by knockdown of autophagy-related gene 3 ( Atg3 ) 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-PKCδ T505 i.e., p-PKD S744/S748 and p-PKD S916 . 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. Graphical Abstract","journal":"GeroScience","year":2025,"id":532232,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9482,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":700534,"name":"Seul‐Ki Park","orcid":"0000-0001-7027-7679","position":1,"is_corresponding":false},{"id":700538,"name":"Sohom Mookherjee","orcid":"0000-0003-2785-1801","position":2,"is_corresponding":false},{"id":920663,"name":"Emily C. Peters","orcid":"0000-0001-7672-3510","position":3,"is_corresponding":false},{"id":969171,"name":"Paulo W. Pires","orcid":"0000-0001-5972-4554","position":4,"is_corresponding":false},{"id":355395,"name":"J. David Symons","orcid":"0000-0003-2021-4770","position":5,"is_corresponding":false},{"id":700533,"name":"Jae Min Cho","orcid":"0000-0002-4461-6945","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:51:23.237536Z","pmid":"40220153","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}