biostudies-literatureKwak EAU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesNIDA NIH HHSNCI NIH HHSNIGMS NIH HHS1326https://www.ebi.ac.uk/biostudies/studies/S-EPMC8921520biostudies-literatureUnknown13(1)Defective angiogenesis underlies over 50 malignant, ischemic and inflammatory disorders yet long-term therapeutic applications inevitably fail, thus highlighting the need for greater understanding of the vast crosstalk and compensatory mechanisms. Based on proteomic profiling of angiogenic endothelial components, here we report β<sub>IV</sub>-spectrin, a non-erythrocytic cytoskeletal protein, as a critical regulator of sprouting angiogenesis. Early loss of endothelial-specific β<sub>IV</sub>-spectrin promotes embryonic lethality in mice due to hypervascularization and hemorrhagic defects whereas neonatal depletion yields higher vascular density and tip cell populations in developing retina. During sprouting, β<sub>IV</sub>-spectrin expresses in stalk cells to inhibit their tip cell potentiNature communicationsβ<sub>IV</sub>-spectrin as a stalk cell-intrinsic regulator of VEGF signaling.PMC8921520P30 DA051355GM128055P30 CA023074R01 CA219495R01 GM128055Lee YSLargent-Milnes TAhmed TCruz-Flores PVanderah TWLanglais PRMohler PJKwak EARamonett ALochhead JJPan CCKumar SHund TJLee NYMouneimne GMythreye KGeorgieva TGOrtiz HREllis NAfalseβ<sub>IV</sub>-spectrin as a stalk cell-intrinsic regulator of VEGF signaling.Defective angiogenesis underlies over 50 malignant, ischemic and inflammatory disorders yet long-term therapeutic applications inevitably fail, thus highlighting the need for greater understanding of the vast crosstalk and compensatory mechanisms. Based on proteomic profiling of angiogenic endothelial components, here we report β<sub>IV</sub>-spectrin, a non-erythrocytic cytoskeletal protein, as a critical regulator of sprouting angiogenesis. Early loss of endothelial-specific β<sub>IV</sub>-spectrin promotes embryonic lethality in mice due to hypervascularization and hemorrhagic defects whereas neonatal depletion yields higher vascular density and tip cell populations in developing retina. During sprouting, β<sub>IV</sub>-spectrin expresses in stalk cells to inhibit their tip cell potenti2022-01-01T00:00:00Z2022 Mar2025-04-04T13:18:34.097Z2025-04-04T13:18:34.097ZS-EPMC89215203528856810.1038/s41467-022-28933-1