{"doi":"10.1101/2023.12.04.569948","title":"Targeting endothelial FOXO1 protects diabetic β-cells and improves wound healing","abstract":"Abstract The forkhead box O1 (FOXO1) transcription factor plays critical roles in regulating not only metabolic activity but also angiogenesis in the vascular endothelium 1–4 . Our previous studies show that epsin endocytic adaptors can regulate both angiogenesis and lymphangiogenesis 5–7 . Endothelial cells (ECs) lining the inside of blood vessels are continuously exposed to circulating insulin and insulin-like growth factors (IGFs). Emerging evidences suggest that ECs can affect β-cell function 8–11 . Excessive IGF2, especially elevated local IGF2 levels in islets, may represent a risk factor for developing diabetes 12–15 ; however, the underlying molecular mechanisms by which aberrant angiogenesis and endothelium-derived factors regulate pancreatic β-cell function in diabetes remain unclear. Here, we report that the pancreas of diabetic patients as well as the pancreas, skin, and plasma of streptozotocin/high fat diet (STZ/HFD)-induced diabetic mice and db/db mice contains excess IGF2, which can lead to β-cell dysfunction and apoptosis. Single-cell transcriptomics combined with mass spectrometry analysis reveal that endothelial-specific knockout of FOXO1 increases circulating soluble and cell-membrane or intracellular expression levels of IGF type 2 receptor (IGF2R) and CCCTC-binding factor (CTCF), while decreasing IGF2 levels in diabetes. Both IGFR2 15–17 and CTCF 18–21 can reduce IGF2 levels and may ameliorate β-cell decline associated with excess IGF2 in diabetes. Furthermore, depletion of FOXO1, epsins, or knockdown of ULK1 inhibits autophagy formation in ECs, preventing degradation of vascular endothelial growth factor receptor 2 (VEGFR2) to promote angiogenesis and improve wound healing in diabetes. Our findings reveal that endothelial FOXO1 regulates epsin-dependent angiogenesis and affects β-cell function and fate through CTCF and IGF2-IGF2R, providing a potential strategy for ameliorating diabetes and accelerating cutaneous wound healing.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":414644,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"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":459573,"name":"Kui Cui","orcid":"0000-0003-2615-4932","position":1,"is_corresponding":false},{"id":481230,"name":"Bo Zhu","orcid":"0000-0002-4001-6045","position":2,"is_corresponding":false},{"id":506679,"name":"Yao Wei Lu","orcid":"0000-0001-6200-2974","position":3,"is_corresponding":false},{"id":669363,"name":"Liang Sun","orcid":"0000-0002-0321-9222","position":4,"is_corresponding":false},{"id":1196262,"name":"Qianyi Ma","orcid":"0009-0007-7835-8327","position":5,"is_corresponding":false},{"id":1196595,"name":"Ashish Jian","orcid":null,"position":6,"is_corresponding":false},{"id":243188,"name":"Daniel Osorio","orcid":"0000-0003-4424-8422","position":7,"is_corresponding":false},{"id":506997,"name":"Xinlei Gao","orcid":"0000-0002-8813-6329","position":8,"is_corresponding":false},{"id":1196596,"name":"Yanqian Li","orcid":null,"position":9,"is_corresponding":false},{"id":410111,"name":"Sudarshan Bhattacharjee","orcid":"0000-0002-3607-9967","position":10,"is_corresponding":false},{"id":475579,"name":"Haojie Fu","orcid":"0000-0001-9561-3747","position":11,"is_corresponding":false},{"id":475580,"name":"Amy E. 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