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Endothelial tip/stalk cell selection requires BMP9-induced β(IV)-spectrin expression during sprouting angiogenesis

β(IV)-Spectrin is a membrane cytoskeletal protein with specialized roles in the nervous system and heart. Recent evidence also indicates a fundamental role for β(IV)-spectrin in angiogenesis as its endothelial-specific gene deletion in mice enhances embryonic lethality due to hypervascularization an...

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Detalles Bibliográficos
Autores principales: Ahmed, Tasmia, Ramonett, Aaron, Kwak, Eun-A, Kumar, Sanjay, Flores, Paola Cruz, Ortiz, Hannah R., Langlais, Paul R., Hund, Thomas J., Mythreye, Karthikeyan, Lee, Nam Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295478/
https://www.ncbi.nlm.nih.gov/pubmed/37126382
http://dx.doi.org/10.1091/mbc.E23-02-0064
Descripción
Sumario:β(IV)-Spectrin is a membrane cytoskeletal protein with specialized roles in the nervous system and heart. Recent evidence also indicates a fundamental role for β(IV)-spectrin in angiogenesis as its endothelial-specific gene deletion in mice enhances embryonic lethality due to hypervascularization and hemorrhagic defects. During early vascular sprouting, β(IV)-spectrin is believed to inhibit tip cell sprouting in favor of the stalk cell phenotype by mediating VEGFR2 internalization and degradation. Despite these essential roles, mechanisms governing β(IV)-spectrin expression remain unknown. Here we identify bone morphogenetic protein 9 (BMP9) as a major inducer of β(IV)-spectrin gene expression in the vascular system. We show that BMP9 signals through the ALK1/Smad1 pathway to induce β(IV)-spectrin expression, which then recruits CaMKII to the cell membrane to induce phosphorylation-dependent VEGFR2 turnover. Although BMP9 signaling promotes stalk cell behavior through activation of hallmark stalk cell genes ID-1/3 and Hes-1 and Notch signaling cross-talk, we find that β(IV)-spectrin acts upstream of these pathways as loss of β(IV)-spectrin in neonate mice leads to retinal hypervascularization due to excessive VEGFR2 levels, increased tip cell populations, and strong Notch inhibition irrespective of BMP9 treatment. These findings demonstrate β(IV)-spectrin as a BMP9 gene target critical for tip/stalk cell selection during nascent vessel sprouting.