{"doi":"10.2337/db09-1507","title":"High-Mobility Group Box-1 Protein Promotes Angiogenesis After Peripheral Ischemia in Diabetic Mice Through a VEGF-Dependent Mechanism","abstract":"<jats:sec>\n                  <jats:title>OBJECTIVE</jats:title>\n                  <jats:p>High-mobility group box-1 (HMGB1) protein is a nuclear DNA-binding protein released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. Diabetic human and mouse tissues contain lower levels of HMGB1 than their normoglycemic counterparts. Deficient angiogenesis after ischemia contributes to worse outcomes of peripheral arterial disease in patients with diabetes. To test the hypothesis that HMGB1 enhances ischemia-induced angiogenesis in diabetes, we administered HMGB1 protein in a mouse hind limb ischemia model using diabetic mice.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>RESEARCH DESIGN AND METHODS</jats:title>\n                  <jats:p>After the induction of diabetes by streptozotocin, we studied ischemia-induced neovascularization in the ischemic hind limb of normoglycemic, diabetic, and HMGB1-treated diabetic mice.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS</jats:title>\n                  <jats:p>We found that the perfusion recovery was significantly attenuated in diabetic mice compared with normoglycemic control mice. Interestingly, HMGB1 protein expression was lower in the ischemic tissue of diabetic mice than in normoglycemic mice. Furthermore, we observed that HMGB1 administration restored the blood flow recovery and capillary density in the ischemic muscle of diabetic mice, that this process was associated with the increased expression of vascular endothelial growth factor (VEGF), and that HMGB1-induced angiogenesis was significantly reduced by inhibiting VEGF activity.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS</jats:title>\n                  <jats:p>The results of this study show that endogenous HMGB1 is crucial for ischemia-induced angiogenesis in diabetic mice and that HMGB1 protein administration enhances collateral blood flow in the ischemic hind limbs of diabetic mice through a VEGF-dependent mechanism.</jats:p>\n               </jats:sec>","journal":"Diabetes","year":2010,"id":626563,"datarank":0.7254422860427218,"base_score":4.836281906951478,"endowment":4.836281906951478,"self_citation_contribution":0.7254422860427218,"citation_network_contribution":0.0,"self_endowment_contribution":0.7254422860427218,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":125,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1620800,"name":"Giuseppe Straface","orcid":null,"position":1,"is_corresponding":false},{"id":796021,"name":"Raimondo De Cristofaro","orcid":"0000-0002-8066-8849","position":2,"is_corresponding":false},{"id":1580226,"name":"Stefano Lancellotti","orcid":null,"position":3,"is_corresponding":false},{"id":1181535,"name":"Paola Rizzo","orcid":"0000-0002-3375-3119","position":4,"is_corresponding":false},{"id":1354286,"name":"Vincenzo Arena","orcid":"0000-0002-4363-6311","position":5,"is_corresponding":false},{"id":1354695,"name":"Egidio Stigliano","orcid":null,"position":6,"is_corresponding":false},{"id":1620803,"name":"Giovanni Pecorini","orcid":null,"position":7,"is_corresponding":false},{"id":1620804,"name":"Kensuke Egashira","orcid":null,"position":8,"is_corresponding":false},{"id":971900,"name":"Giulia De Angelis","orcid":"0000-0002-4471-6428","position":9,"is_corresponding":false},{"id":1620805,"name":"Giovanni Ghirlanda","orcid":null,"position":10,"is_corresponding":false},{"id":520867,"name":"Andrea Flex","orcid":"0000-0003-2664-4165","position":11,"is_corresponding":false},{"id":520868,"name":"Federico Biscetti","orcid":"0000-0001-7449-657X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"High-Mobility Group Box-1 Protein Promotes Angiogenesis After Peripheral Ischemia in Diabetic Mice Through a VEGF-Dependent Mechanism","abstract":"<jats:sec>\n                  <jats:title>OBJECTIVE</jats:title>\n                  <jats:p>High-mobility group box-1 (HMGB1) protein is a nuclear DNA-binding protein released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. Diabetic human and mouse tissues contain lower levels of HMGB1 than their normoglycemic counterparts. Deficient angiogenesis after ischemia contributes to worse outcomes of peripheral arterial disease in patients with diabetes. To test the hypothesis that HMGB1 enhances ischemia-induced angiogenesis in diabetes, we administered HMGB1 protein in a mouse hind limb ischemia model using diabetic mice.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>RESEARCH DESIGN AND METHODS</jats:title>\n                  <jats:p>After the induction of diabetes by streptozotocin, we studied ischemia-induced neovascularization in the ischemic hind limb of normoglycemic, diabetic, and HMGB1-treated diabetic mice.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS</jats:title>\n                  <jats:p>We found that the perfusion recovery was significantly attenuated in diabetic mice compared with normoglycemic control mice. Interestingly, HMGB1 protein expression was lower in the ischemic tissue of diabetic mice than in normoglycemic mice. Furthermore, we observed that HMGB1 administration restored the blood flow recovery and capillary density in the ischemic muscle of diabetic mice, that this process was associated with the increased expression of vascular endothelial growth factor (VEGF), and that HMGB1-induced angiogenesis was significantly reduced by inhibiting VEGF activity.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS</jats:title>\n                  <jats:p>The results of this study show that endogenous HMGB1 is crucial for ischemia-induced angiogenesis in diabetic mice and that HMGB1 protein administration enhances collateral blood flow in the ischemic hind limbs of diabetic mice through a VEGF-dependent mechanism.</jats:p>\n               </jats:sec>","is_dataset_classified":null,"base_score":4.836281906951478,"endowment":4.836281906951478,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"20200317","pmcid":"PMC2874711","openalex_id":"https://openalex.org/W2157820814","authors":[],"funders":[],"total_grants":0,"fwci":5.6396,"citation_percentile":0.9700503,"influential_citations":0,"citation_trend":[{"year":2012,"count":11},{"year":2013,"count":10},{"year":2014,"count":9},{"year":2015,"count":13},{"year":2016,"count":5},{"year":2017,"count":9},{"year":2018,"count":7},{"year":2019,"count":3},{"year":2020,"count":5},{"year":2021,"count":9},{"year":2022,"count":8},{"year":2023,"count":16},{"year":2024,"count":3},{"year":2025,"count":3},{"year":2026,"count":2}],"oa_status":"hybrid","license":"cc-by-nc-nd","oa_locations":[{"url":"https://diabetesjournals.org/diabetes/article-pdf/59/6/1496/399357/zdb00610001496.pdf","host_type":"journal"},{"url":"https://diabetesjournals.org/diabetes/article-pdf/59/6/1496/399357/zdb00610001496.pdf","host_type":"publisher"},{"url":"https://journals.org/diabetes/diabetes/article-pdf/59/6/1496/399357/zdb00610001496.pdf","host_type":"publisher"},{"url":"https://doi.org/10.2337/db09-1507","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/20200317","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2874711","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC2874711","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC2874711?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Advanced Glycation End Products research","Angiogenesis and VEGF in Cancer","S100 Proteins and Annexins","Animals","Blood Flow Velocity","Diabetes Mellitus, Experimental","HMGB1 Protein","Hindlimb","Humans","Ischemia","Male","Mice","Mice, Inbred C57BL","Muscle, Skeletal","Neovascularization, Pathologic","Neovascularization, Physiologic","Vascular Endothelial Growth Factor A"],"mesh_terms":["Animals","Blood Flow Velocity","Diabetes Mellitus, Experimental","Hindlimb","Humans","Ischemia","Male","Mice, Inbred C57BL","Neovascularization, Pathologic","Muscle, Skeletal","Neovascularization, Physiologic","HMGB1 Protein","Vascular Endothelial Growth Factor A","Mice"],"keywords":["HMGB1","Angiogenesis","Ischemia","Medicine","Endocrinology","Perfusion","Diabetes mellitus","Internal medicine","Neovascularization","Vascular endothelial growth factor","Hindlimb","Inflammation","VEGF receptors"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-04T14:21:29.353090Z","pmid":null,"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":[]}