Combined deficiency of Notch1 and Notch3 causes pericyte dysfunction, models CADASIL, and results in arteriovenous...

Area of Science:

• Vascular biology
• Cell signaling
• Developmental biology

Background:

• Pericytes are essential for blood vessel stability and their dysfunction is implicated in various diseases.
• The role of Notch signaling in pericyte biology and its contribution to vascular pathologies remains incompletely understood.

Purpose of the Study:

• To investigate the role of Notch signaling, specifically Notch1 and Notch3, in regulating pericyte function during angiogenesis.
• To determine how combined Notch1 and Notch3 deficiency affects pericyte-endothelial interactions and vascular development.

Main Methods:

• Utilized Notch1(+/-); Notch3(-/-) mice to study the combined effects of Notch1 and Notch3 deficiency.
• Analyzed pericyte coverage, endothelial cell activation, and vascular basement membrane formation in the retinal vasculature.
• Examined the development of arteriovenous malformations and stroke-like phenotypes in mutant mice.

Main Results:

• Combined Notch1 and Notch3 deficiency altered pericyte-endothelial interactions and reduced retinal pericyte coverage.
• Notch1 and Notch3 cooperate to ensure proper vascular basement membrane formation and endothelial cell quiescence.
• Loss of Notch signaling exacerbated endothelial cell activation and led to arteriovenous malformations and stroke hallmarks.

Conclusions:

• Notch signaling, particularly through Notch1 and Notch3, is a key regulator of pericyte function essential for vascular stability.
• Notch deficiency compromises pericyte function, contributing to the pathogenesis of vascular pathologies including stroke and retinopathy.