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

Cellular communication network factor 1 (CCN1) is a dynamically expressed, matricellular protein required for vascular development and tissue repair. The gene is a presumed target of Yes-associated protein (YAP), a transcriptional coactivator that regulates cell growth and organ size. Herein, we demonstrate that the promoter is indeed a direct genomic target of YAP in endothelial cells (ECs) of new blood vessel sprouts and that deficiency in mice downregulates and alters cytoskeletal and mitogenic gene expression. Interestingly, overexpression in cultured ECs inactivates YAP in a negative feedback and causes its nuclear exclusion. Accordingly, EC-specific deletion of the gene in mice mimics a gain-of-function phenotype, characterized by EC hyperproliferation and blood vessel enlargement. CCN1 brings about its effect by providing cells with a soft compliant matrix that creates YAP-repressive cytoskeletal states. Concordantly, pharmacological inhibition of cell stiffness recapitulates the deletion vascular phenotype. Furthermore, adeno-associated virus-mediated expression of reversed the pathology of YAP hyperactivation and the subsequent aberrant growth of blood vessels in mice with ischemic retinopathy. Our studies unravel a new paradigm of functional interaction between CCN1 and YAP and underscore the significance of their interplay in the pathogenesis of neovascular diseases.