{"doi":"10.1016/j.vph.2025.107530","title":"Sodium-glucose cotransporter 2 inhibition restores testicular microvascular perfusion via endothelial signaling in a large animal model of metabolic syndrome and heart failure","abstract":"OBJECTIVE: This study evaluates the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition on testicular microvascular function and vascular signaling pathways in a swine model of metabolic syndrome (MetS) and ischemic cardiomyopathy (ICM). METHODS: Eleven male Yorkshire swine were fed a high-fat diet to induce MetS. At 11 weeks, ICM was induced by placing an ameroid constrictor around the left circumflex artery. After a two-week stabilization period, swine were randomized into a high-fat control (HFC) or canagliflozin-treated (HCAN, 300 mg/day) group for five weeks. Terminal harvests were performed to assess testicular perfusion, endothelial function markers, and pro-apoptotic signaling. RESULTS: Canagliflozin (CAN) significantly improved testicular perfusion (p = 0.0134). Molecular analysis showed a significant increase in p-AMPK/AMPK ratio (p = 0.0483), indicating enhanced metabolic and endothelial signaling, and a significant reduction in BAD/BCL2 ratio (p = 0.0095), consistent with a shift toward anti-apoptotic signaling. The p-eNOS/eNOS ratio trended upward in treated animals (p = 0.1007), suggesting potential augmentation of nitric oxide-mediated vasodilation. Total ERK expression was also increased (p = 0.0201), supporting engagement of MAPK pathways. CONCLUSION: SGLT2 inhibition improved testicular microvascular perfusion and modulated key signaling ratios, including increased p-AMPK/AMPK and reduced BAD/BCL2, with a trend toward higher p-eNOS/eNOS. These findings demonstrate that canagliflozin promotes vascular survival pathways in peripheral tissues, underscoring its vasculoprotective potential beyond the myocardium.","journal":"Vascular Pharmacology","year":2025,"id":546237,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"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":1275146,"name":"Christopher Stone","orcid":"0000-0002-9621-5334","position":1,"is_corresponding":false},{"id":930600,"name":"Dwight D. Harris","orcid":"0000-0001-8289-2740","position":2,"is_corresponding":false},{"id":1437981,"name":"Kelsey Muir","orcid":"0000-0001-8768-5468","position":3,"is_corresponding":false},{"id":939660,"name":"Keertana Yalamanchili","orcid":null,"position":4,"is_corresponding":false},{"id":381664,"name":"Nicholas Sellke","orcid":"0000-0001-9378-8666","position":5,"is_corresponding":false},{"id":371889,"name":"Frank W. Sellke","orcid":"0000-0002-8886-801X","position":6,"is_corresponding":false},{"id":1222955,"name":"Jad Hamze","orcid":"0009-0000-2758-8746","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:53:32.285899Z","pmid":"40848868","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":[]}