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

ABSTRACT

Cellular communication network factor 1 (CCN1) is a dynamically expressed, matricellular protein required for vascular development and tissue repair. The CCN1 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 CCN1 promoter is indeed a direct genomic target of YAP in endothelial cells (ECs) of new blood vessel sprouts and that YAP deficiency in mice downregulates CCN1 and alters cytoskeletal and mitogenic gene expression. Interestingly, CCN1 overexpression in cultured ECs inactivates YAP in a negative feedback and causes its nuclear exclusion. Accordingly, EC-specific deletion of the CCN1 gene in mice mimics a YAP 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 CCN1 deletion vascular phenotype. Furthermore, adeno-associated virus-mediated expression of CCN1 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.

KEYWORDS:

• CCN1
• YAP
• angiogenesis
• extracellular matrix
• ischemic retinopathy

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Articles of Significant Interest in This Issue

ACKNOWLEDGMENT

We thank Genesis Lopez and Melanie Vinueza for their technical contributions. We thank all past and present lab members for their contributions to the generation and characterization of genetically modified animals and for helpful discussions during the preparation of the manuscript. We are grateful to Fernando Camargo (Harvard Stem Cell Institute) for providing YAP^flox/flox mice and K. M. Hahn (UNC) for the generous gift of Rho GTPase dominant negative forms.

This work was supported in part by grants from the National Eye Institute of the National Institutes of Health (grants EY022091-05A1 and EY024998) to B.C.