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Endothelial Deficiency of the Extracellular Matrix Protein CCN1 Alters Developmental and Pathological Angiogenesis
Author(s) -
Chaqour Brahim,
Krupska Izabela,
Yan Lulu,
Lau Lester,
Grant Maria,
Chintala Hemabindu
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.719.2
Subject(s) - microbiology and biotechnology , angiogenesis , cyr61 , biology , matricellular protein , proto oncogene tyrosine protein kinase src , protein tyrosine phosphatase , vascular endothelial growth factor , extracellular matrix , signal transduction , chemistry , cancer research , growth factor , biochemistry , receptor , ctgf , vegf receptors
CCN1 is a secreted cysteine‐rich and integrin‐binding matricellular protein required for proper cardiovascular development. However, our understanding of the cellular origins and activities of this molecule is incomplete. Here, we show that CCN1 is predominantly expressed in angiogenic endothelial cells (ECs) at the leading front of actively growing vessels in the mouse retina. Endothelial deletion of CCN1 in mice using a Cre/Lox system is associated with EC hyperplasia and formation of dense retinal vascular networks lacking the normal hierarchical arrangement of arterioles, capillaries and venules. CCN1 is a product of an immediate‐early gene that is transcriptionally induced in ECs in response to stimulation by vascular endothelial growth factor (VEGF). We found that CCN1 activity is integrated with VEGF receptor 2 (VEGF‐R2) activation and downstream signaling pathways required for tubular network formation. CCN1 increased the expression of and association between Src homology 2 domain–containing protein tyrosine phosphatase‐1 (SHP‐1) and VEGF‐R2 which leads to rapid dephosphorylation of VEGF‐R2 tyrosine preventing EC hyperproliferation.Concordantly, ectopic expression of CCN1 prevents the exuberant ischemia‐induced retinal neovascularization in an oxygen‐induced retinopathy model by altering the balance of activation of VEGF‐R2 and SHP‐1. These data highlight novel functions of CCN1 as a naturally optimized molecule fine controlling key processes in physiological angiogenesis and safeguarding against aberrant angiogenic responses. Supported by NEI‐NIH grant EY022091‐01