A functional antagonism between RhoJ and Cdc42 regulates fibronectin remodelling during angiogenesis

Area of Science:

• Molecular Biology
• Cell Biology
• Vascular Biology

Background:

• Angiogenesis, the formation of new blood vessels, is crucial for development and disease.
• Endothelial cell migration and polarity are key to angiogenesis, regulated by Rho GTPases.
• RhoJ, an endothelium-enriched Rho GTPase, shares similarities with Cdc42.

Purpose of the Study:

• To investigate the role of RhoJ in angiogenesis and its interaction with Cdc42.
• To elucidate the mechanism by which RhoJ regulates fibronectin fibrillogenesis.
• To understand the functional antagonism between RhoJ and Cdc42 in endothelial cells.

Main Methods:

• Co-immunoprecipitation assays to study α5β1 integrin and RhoJ interaction.
• Analysis of fibronectin fibril formation in endothelial cells.
• Phenotypic analysis of RhoJ null mice.

Main Results:

• RhoJ co-traffics with α5β1 integrin and represses its internalization, reducing fibronectin fibril formation.
• RhoJ's function in fibrillogenesis opposes that of Cdc42.
• Competition for the shared effector PAK3 explains the opposing roles of RhoJ and Cdc42.
• RhoJ null mice exhibit excessive fibronectin deposition in retinal vessels.

Conclusions:

• A functional antagonism exists between RhoJ and Cdc42, mediated by competition for PAK3.
• This antagonism restricts fibronectin remodeling to sites of active angiogenesis, facilitating provisional matrix formation.
• RhoJ-mediated repression of fibronectin remodeling may be atheroprotective in quiescent vessels.