ADAM10 and ADAM17 have opposite roles during sprouting angiogenesis.

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Angiogenesis involves endothelial tip cells expressing delta-like 4 (DLL4) to activate Notch signaling in stalk cells, suppressing sprouting.
• Vascular endothelial growth factor (VEGF) activates A disintegrins and metalloproteinases (ADAMs) to shed Notch ectodomain, influencing angiogenesis.
• ADAM10 and ADAM17 are implicated in Notch signaling, but their distinct roles in angiogenesis require clarification.

Purpose of the Study:

• To elucidate the specific roles of ADAM10 and ADAM17 activity in the process of angiogenesis.
• To investigate the mechanisms by which ADAM10 and ADAM17 influence blood vessel formation beyond Notch signaling.

Main Methods:

• Inhibition of ADAM10 or ADAM17 activity and combined attenuation in mouse retinas.
• Analysis of retinal blood vessel morphology in ADAM17 hypomorphic mice.
• Angiogenesis proteome assay and tube formation assays.
• Overexpression of ADAM17 and use of Thrombospondin 1 (TSP1) inhibitor LSKL.

Main Results:

• ADAM10 or γ-secretase inhibition promoted vascular sprouting and density, while combined ADAM10 and ADAM17 inhibition reduced it.
• ADAM17 activity is essential for angiogenesis, but its inhibition did not replicate the effects of Notch blockage.
• ADAM17 inhibition led to increased Thrombospondin 1 (TSP1) expression, a known angiogenesis inhibitor, while ADAM10 inhibition did not.
• ADAM17 overexpression decreased TSP1, and TSP1 inhibition rescued angiogenesis under ADAM17 inhibition.

Conclusions:

• ADAM10 and ADAM17 exhibit opposing functions in sprouting angiogenesis, potentially independent of Notch signaling.
• ADAM17 regulates angiogenesis partly through modulation of TSP1 expression.
• These findings highlight distinct roles for ADAM10 and ADAM17 in controlling blood vessel formation via differential expression of anti-angiogenic factors.