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

Area of Science:

• Molecular Biology
• Developmental Biology
• Cell Biology

Background:

• β_IV-spectrin is a membrane protein vital for nervous system and heart function.
• Endothelial β_IV-spectrin plays a key role in angiogenesis, with its absence causing hypervascularization.
• β_IV-spectrin is thought to regulate tip cell sprouting by promoting VEGFR2 internalization.

Purpose of the Study:

• To identify the regulatory mechanisms of β_IV-spectrin expression in the vascular system.
• To elucidate the role of β_IV-spectrin in tip/stalk cell selection during angiogenesis.

Main Methods:

• Investigated BMP9 signaling pathways (ALK1/Smad1) in relation to β_IV-spectrin expression.
• Utilized mouse models with endothelial-specific gene deletion of β_IV-spectrin.
• Analyzed VEGFR2 internalization, CaMKII recruitment, and expression of stalk cell markers (ID-1/3, Hes-1) and Notch signaling.

Main Results:

• BMP9 was identified as a primary inducer of β_IV-spectrin gene expression via the ALK1/Smad1 pathway.
• BMP9-induced β_IV-spectrin recruits CaMKII, leading to VEGFR2 phosphorylation-dependent turnover.
• Loss of β_IV-spectrin resulted in retinal hypervascularization, elevated VEGFR2, increased tip cells, and Notch inhibition, independent of BMP9 treatment.

Conclusions:

• β_IV-spectrin is a direct BMP9 target gene essential for regulating vascular sprouting.
• β_IV-spectrin acts upstream of BMP9-mediated stalk cell differentiation pathways.
• β_IV-spectrin is critical for maintaining vascular homeostasis by controlling tip/stalk cell fate.