CCN1 is a heparin and integrin‐binding matricellular protein which localizes pericellularly and acts primarily on cells that produce it. CCN1 is highly expressed at sites of active angiogenesis and ...tissue repair. Our studies in conditional knockout mouse models, demonstrate that endothelium‐specific deletion of the CCN1 gene results in severe vascular defects, most notably uncontrolled angiogenic sprouting and increased endothelial cell (EC) proliferation, resulting in the formation of a denser, widely lumenized vascular network. In this study, we investigated the regulatory mechanisms and signaling pathways involved in CCN1 gene expression and activity during angiogenesis. We found that the CCN1 gene is a target of the transcriptional coactivator Yes‐Associated protein (YAP), which acts in concert with other co‐activators such as myocardin‐related transcription factor (MRTF)‐A to activate the CCN1 promoter in angiogenic ECs. Loss of YAP function in mice is associated with reduced CCN1 promoter enrichment with YAP and decreased CCN1 gene expression. YAP is a key checkpoint of the Hippo pathway controlling cell growth, differentiation and cell‐cell junctions. It comprises a kinase cascade that inactivates by phosphorylation YAP leading to its cytoplasmic sequestration and growth inhibition. Loss of function of CCN1 in mice was associated with accumulation of active nonphosphorylated YAP in developing blood vessels. Consequently, growing ECs incorporate into preformed vessels and are no longer directed toward angiogenic sprouts, resulting in the formation of a thicker denser vasculature. In cultured ECs, a sustained expression of CCN1 through adenoviral gene transfer increases YAP phosphorylation and reduced its localization into the nucleus. CCN1‐integrin signaling through focal adhesion and the actin cytoskeleton provides the cells with a soft compliant matrix putting them in in low contractility, YAP repressive cytoskeletal states. This crosstalk between CCN1 and YAP regulates phenotypical plasticity of ECs and promotes correct sprouting and branching patterns of developing blood vessels.
Support or Funding Information
R01EY022091‐05A1
R01EY024998‐01A1
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.
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