Endothelial tip/stalk cell selection requires BMP9-induced βIV-spectrin expression during sprouting angiogenesis

Tasmia Ahmed, Aaron Ramonett, Eun A. Kwak, Sanjay Kumar, Paola Cruz Flores, Hannah R. Ortiz, Paul R. Langlais, Thomas J. Hund, Karthikeyan Mythreye, Nam Y. Lee

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


βIV-Spectrin is a membrane cytoskeletal protein with specialized roles in the nervous system and heart. Recent evidence also indicates a fundamental role for βIV-spectrin in angiogenesis as its endothelial-specific gene deletion in mice enhances embryonic lethality due to hypervascularization and hemorrhagic defects. During early vascular sprouting, βIVspectrin 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 βIV-spectrin expression remain unknown. Here we identify bone morphogenetic protein 9 (BMP9) as a major inducer of βIV-spectrin gene expression in the vascular system. We show that BMP9 signals through the ALK1/Smad1 pathway to induce βIV-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 βIV-spectrin acts upstream of these pathways as loss of βIV-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 βIV-spectrin as a BMP9 gene target critical for tip/stalk cell selection during nascent vessel sprouting.

Original languageEnglish (US)
Article numberar72
JournalMolecular biology of the cell
Issue number7
StatePublished - Jun 1 2023

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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