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Brahim Chaqour, Maria Grant, Jinog Choi, Izabella Krupska, Lulu Yan, Hemabindu Chintala; Control of physiological and pathological angiogenesis in the retina by the matricellular protein CCN1. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3556. doi: https://doi.org/.
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CCN1 is a non-structural bioactive extracellular matrix-associated heparin- and integrin-binding protein whose expression is associated with sites of angiogenesis and tissue repair. In the retina, CCN1 protein was prominently expressed at the leading front of actively growing vessels. Conventional CCN1 gene deletion in mice resulted in major vascular defects and embryonic lethality. Here we used endothelial-specific inducible gene targeting strategy in mice to define the function of CCN1 in retinal vascular development and pathology.
Inducible loss-of-function of CCN1 in the endothelium was carried out by crossing mice carrying floxed CCN1 alleles with tamoxifen-activated Cdh5(PAC)-CreERT2 mice. Retinal vascular alterations were characterized at postnatal day (P) 4 and P7 upon injection of tamoxifen using immunohistochemical and biochemical techniques. Effects of CCN1-loss-of-function on retinal neovascularization were determined in the mouse model of oxygen-induced retinopathy (OIR).
Endothelium-specific inactivation of CCN1 resulted in a dense vascular network with increased endothelial cell (EC) proliferation and apparent coalescence of retinal vessels leading to loss of typical features of the retinal vascular architecture. Endothelial tubes were devoid of pericyte coverage. Defects in angiogenic sprouting were linked to increased activation of vascular endothelial growth factor (VEGF) receptor 2 and altered downstream Notch signaling activity at the distal growing end of new angiogenic vessels. Subsequently, more ECs incorporate into the wall of forming tubes rather than into new sprouts and branches. These changes were directly coupled to enhanced VEGF signaling mechanisms required for EC lumen and tube network formation. In the mouse model of OIR, ectopic expression of CCN1 promoted normal vessel formation while suppressing abnormal pathological neovascularization by increasing resistance to vaso-obliteration and fine-tuning the bioavailability of VEGF.
CCN1 is an angiogenic factor required for normal retinal vessel morphogenesis and stabilization during normal development as well as during progression of pathology. CCN1 activity may involve, at least in part, shaping gradients of VEGF activity in areas of uniform ligand expression.
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