CCN1-Yes-Associated Protein Feedback Loop Regulates Physiological and Pathological Angiogenesis.

Area of Science:

• Molecular Biology
• Cell Biology
• Vascular Biology

Background:

• Cellular communication network factor 1 (CCN1) is a matricellular protein vital for vascular development and tissue repair.
• Yes-associated protein (YAP) is a transcriptional coactivator regulating cell growth and organ size, with CCN1 presumed as a target.

Purpose of the Study:

• To elucidate the functional interaction between CCN1 and YAP in endothelial cells.
• To investigate the role of CCN1-YAP interplay in neovascularization and related diseases.

Main Methods:

• Demonstrated direct YAP binding to the CCN1 promoter in endothelial cells.
• Utilized mouse models with YAP deficiency and CCN1 gene deletion/overexpression.
• Investigated CCN1's effect on cell stiffness and YAP activity.
• Employed adeno-associated virus-mediated CCN1 delivery in an ischemic retinopathy model.

Main Results:

• YAP directly targets the CCN1 promoter in sprouting endothelial cells; YAP deficiency downregulates CCN1 and alters gene expression.
• CCN1 overexpression negatively feedbacks on YAP, causing nuclear exclusion.
• CCN1 deletion in mice phenocopies YAP gain-of-function, leading to endothelial cell hyperproliferation and blood vessel enlargement.
• CCN1-induced matrix softening creates YAP-repressive cytoskeletal states; inhibiting cell stiffness mimics CCN1 deletion phenotype.
• CCN1 expression reversed YAP hyperactivation and aberrant neovascularization in ischemic retinopathy.

Conclusions:

• Established a novel paradigm of functional interaction between CCN1 and YAP.
• Highlighted the significance of CCN1-YAP interplay in the pathogenesis of neovascular diseases.
• Demonstrated therapeutic potential of CCN1 in reversing YAP-driven aberrant blood vessel growth.