Abstract
CYR61-CTGF-NOV (CCN)1 is a dynamically expressed extracellular matrix (ECM) protein with critical functions in cardiovascular development and tissue repair. Angiogenic endothelial cells (ECs) are a major cellular source of CCN1 which, once secreted, associates with the ECM and the cell surface and tightly controls the bidirectional flow of information between cells and the surrounding matrix. Endothelium-specific CCN1 deletion in mice using a cre/lox strategy induces EC hyperplasia and causes blood vessels to coalesce into large flat hyperplastic sinuses with no distinctive hierarchical organization. This is consistent with the role of CCN1 as a negative feedback regulator of vascular endothelial growth factor (VEGF) receptor activation. In the mouse model of oxygen-induced retinopathy (OIR), pericytes become the predominant CCN1 producing cells. Pericyte-specific deletion of CCN1 significantly decreases pathological retinal neovascularization following OIR. CCN1 induces the expression of the non-canonical Wnt5a in pericyte but not in EC cultures. In turn, exogenous Wnt5a inhibits CCN1 gene expression, induces EC proliferation and increases hypersprouting. Concordantly, treatment of mice with TNP470, a non-canonical Wnt5a inhibitor, reestablishes endothelial expression of CCN1 and significantly decreases pathological neovascular growth in OIR. Our data highlight the significance of CCN1-EC and CCN1-pericyte communication signals in driving physiological and pathological angiogenesis.
Highlights
The expansion and/or regeneration of functional blood vessels occur by sprouting angiogenesis, which involves a series of key events including formation of new branches by migration and proliferation of endothelial cells (ECs), fusion of sprouts to form circuits and maturation and stabilization of the vascular network through coverage with mural cells such as pericytes[1]
The interaction between ECs and pericytes through direct physical contacts and/or paracrine signaling molecules is an important mode of communication that is critical for vessel homeostasis and remodeling
Our study provided new insights into the mechanisms whereby pericyte-EC crosstalk partakes in pathological angiogenesis
Summary
The expansion and/or regeneration of functional blood vessels occur by sprouting angiogenesis, which involves a series of key events including formation of new branches by migration and proliferation of endothelial cells (ECs), fusion of sprouts to form circuits and maturation and stabilization of the vascular network through coverage with mural cells such as pericytes[1]. This process is accompanied by the simultaneous deposition of a basement membrane (BM), remodeling of blood vessels into morphologically recognizable arteries, capillaries, and veins and pruning of unwanted and dysfunctional branches. We investigate how CCN1 expression, or lack thereof, affects bidirectional signaling between ECs and pericytes and defines the angiogenic outcome under pathological conditions
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