{"doi":"10.1016/j.jbc.2023.103050","title":"The 5-lipoxygenase/cyclooxygenase-2 cross-over metabolite, hemiketal E2, enhances VEGFR2 activation and promotes angiogenesis","abstract":"Consecutive oxygenation of arachidonic acid by 5-lipoxygenase and cyclooxygenase-2 yields the hemiketal eicosanoids, HKE 2 and HKD 2 . Hemiketals stimulate angiogenesis by inducing endothelial cell tubulogenesis in culture; however, how this process is regulated has not been determined. Here, we identify vascular endothelial growth factor receptor 2 (VEGFR2) as a mediator of HKE 2 -induced angiogenesis in vitro and in vivo . We found that HKE 2 treatment of human umbilical vein endothelial cells dose-dependently increased the phosphorylation of VEGFR2 and the downstream kinases ERK and Akt that mediated endothelial cell tubulogenesis. In vivo , HKE 2 induced the growth of blood vessels into polyacetal sponges implanted in mice. HKE 2 -mediated effects in vitro and in vivo were blocked by the VEGFR2 inhibitor vatalanib, indicating that the pro-angiogenic effect of HKE 2 was mediated by VEGFR2. HKE 2 covalently bound and inhibited PTP1B, a protein tyrosine phosphatase that dephosphorylates VEGFR2, thereby providing a possible molecular mechanism for how HKE 2 induced pro-angiogenic signaling. In summary, our studies indicate that biosynthetic cross-over of the 5-lipoxygenase and cyclooxygenase-2 pathways gives rise to a potent lipid autacoid that regulates endothelial cell function in vitro and in vivo . These findings suggest that common drugs targeting the arachidonic acid pathway could prove useful in antiangiogenic therapy.","journal":"Journal of Biological Chemistry","year":2023,"id":353633,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"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":361743,"name":"Juan Antonio Giménez‐Bastida","orcid":"0000-0002-1244-8764","position":1,"is_corresponding":false},{"id":626594,"name":"Paula B. Luis","orcid":"0000-0001-6729-1023","position":2,"is_corresponding":false},{"id":1100767,"name":"Sai H. Presley","orcid":null,"position":3,"is_corresponding":false},{"id":348789,"name":"Robert E. Boer","orcid":"0000-0002-5027-2763","position":4,"is_corresponding":false},{"id":506356,"name":"Manuel Chiusa","orcid":"0000-0002-5017-1153","position":5,"is_corresponding":false},{"id":1044483,"name":"Takahiro Shibata","orcid":"0000-0003-3194-607X","position":6,"is_corresponding":false},{"id":317764,"name":"Gary A. Sulikowski","orcid":"0000-0002-1067-0767","position":7,"is_corresponding":false},{"id":506361,"name":"Ambra Pozzi","orcid":"0000-0001-8502-1481","position":8,"is_corresponding":false},{"id":361746,"name":"Claus Schneider","orcid":"0000-0003-4215-967X","position":9,"is_corresponding":false},{"id":773015,"name":"Fumie Nakashima","orcid":null,"position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T01:13:02.680107Z","pmid":"36813233","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":[]}