Endothelial tip/stalk cell selection requires BMP9-induced ßIV-spectrin expression during sprouting angiogenesis.
Mol Biol Cell
; 34(7): ar72, 2023 06 01.
Article
in En
| MEDLINE
| ID: mdl-37126382
ABSTRACT
ßIV-Spectrin is a membrane cytoskeletal protein with specialized roles in the nervous system and heart. Recent evidence also indicates a fundamental role for ßIV-spectrin in angiogenesis as its endothelial-specific gene deletion in mice enhances embryonic lethality due to hypervascularization and hemorrhagic defects. During early vascular sprouting, ßIV-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 ßIV-spectrin expression remain unknown. Here we identify bone morphogenetic protein 9 (BMP9) as a major inducer of ßIV-spectrin gene expression in the vascular system. We show that BMP9 signals through the ALK1/Smad1 pathway to induce ßIV-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 ßIV-spectrin acts upstream of these pathways as loss of ßIV-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 ßIV-spectrin as a BMP9 gene target critical for tip/stalk cell selection during nascent vessel sprouting.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Spectrin
/
Growth Differentiation Factor 2
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Mol Biol Cell
Journal subject:
BIOLOGIA MOLECULAR
Year:
2023
Document type:
Article