{"doi":"10.1101/2023.11.04.565656","title":"Myeloid Drp1 Deficiency Limits Revascularization in Ischemic Muscles via Inflammatory Macrophage Polarization and Metabolic Reprograming","abstract":"ABSTRACT In the preclinical model of peripheral arterial disease (PAD), M2-like anti-inflammatory macrophage polarization and angiogenesis are required for revascularization. The regulation of cell metabolism and inflammation in macrophages is tightly linked to mitochondrial dynamics. Drp1, a mitochondrial fission protein, has shown context-dependent macrophage phenotypes with both pro- and anti-inflammatory characteristics. However, the role of macrophage Drp1 in reparative neovascularization remains unexplored. Here we show that Drp1 expression was significantly increased in F4/80 + macrophages within ischemic muscle at day 3 after hindlimb ischemia (HLI), an animal model of PAD. Myeloid-specific Drp1 -/- mice exhibited reduced limb perfusion recovery, angiogenesis and muscle regeneration after HLI. These effects were associated with an increase in pro-inflammatory M1-like macrophages, p-NFkB and TNFα, and reduced anti-inflammatory M2-like macrophages and p-AMPK in ischemic muscle of myeloid Drp1 -/- mice. In vitro , Drp1 -/- macrophages under hypoxia serum starvation (HSS), an in vitro PAD model, demonstrated enhanced glycolysis via reducing p-AMPK as well as mitochondrial dysfunction and excessive mitochondrial ROS, resulting in increased M1-gene and reduced M2-gene expression. Conditioned media from HSS-treated Drp1 -/- macrophages exhibited increased secretion of pro-inflammatory cytokines and suppressed angiogenic responses in cultured endothelial cells. Thus, Drp1 deficiency in macrophages under ischemia drives inflammatory metabolic reprogramming and macrophage polarization, thereby limiting revascularization in experimental PAD.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":401467,"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":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":732815,"name":"Vijay C. Ganta","orcid":"0000-0002-2967-8320","position":1,"is_corresponding":false},{"id":636184,"name":"Sudhahar Varadarajan","orcid":"0000-0002-9675-0097","position":2,"is_corresponding":false},{"id":636183,"name":"Dipankar Ash","orcid":"0000-0002-0364-7366","position":3,"is_corresponding":false},{"id":1178425,"name":"Sheela Nagarkoti","orcid":"0000-0002-3707-5036","position":4,"is_corresponding":false},{"id":320641,"name":"Archita Das","orcid":"0000-0001-9372-1904","position":5,"is_corresponding":false},{"id":1178913,"name":"M G McMenamin","orcid":null,"position":6,"is_corresponding":false},{"id":1178914,"name":"Stephanie Kelley","orcid":null,"position":7,"is_corresponding":false},{"id":235265,"name":"Tohru Fukai","orcid":"0000-0001-9864-571X","position":8,"is_corresponding":false},{"id":235266,"name":"Masuko Ushio‐Fukai","orcid":"0000-0001-7048-2381","position":9,"is_corresponding":false},{"id":1178424,"name":"Shikha Yadav","orcid":"0000-0002-9934-9805","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T01:20:12.316631Z","pmid":"37961122","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":[]}