CTGF has a strong and persistent expression in the retinal vasculature Mice lacking CTGF exhibit defects in angiogenesis and blood barrier integrity CTGF-targeted genes include matrix, growth, and transcription cofactors like YAP YAP re-expression partly rescues angiogenic and barriergenic defects of CTGF loss

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.

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Heparan sulfate (HS) is a linear polysaccharide found in almost all animal cells and plays an important role in various biological processes. HS functions mainly via covalently binding to core proteins to form HS proteoglycans (HSPGs), which are heterogeneous in the lengths of the HS chain, the modifications on HS, and the core proteins. The molecular mechanisms underlying HSPG heterogeneity, although widely studied, are not yet fully defined. The expression profiles of HS biosynthesis enzymes and HSPG core proteins likely contribute to the HSPG heterogeneity, but these expression profiles remain poorly characterized. To investigate the expression profiles of genes encoding HS biosynthesis enzymes and HSPG core proteins, we systematically integrated the publicly available RNA sequencing data in mice. To reveal the spatial expression of these genes, we analyzed their expression in 21 mouse tissues. To reveal the temporal expression of these genes, we analyzed their expression at 17 time points during the mouse forebrain development. To determine the cell-type-specific expression of these genes, we obtained their expression profiles in 23 cell types in the mouse cerebral cortex by integrating single nucleus RNA sequencing data. Our findings demonstrate the spatial, temporal, and cell-type-specific expression of genes encoding HS biosynthesis enzymes and HSPG core proteins and represent a valuable resource to the HS research community.