Abstract
CCN1 (CYR61) stimulates active angiogenesis in various tumours, although the mechanism is largely unknown. Here, we report that CCN1 is a key regulator of endothelial tip cell activity in angiogenesis. Microvessel networks and directional vascular cell migration patterns were deformed in ccn1-knockdown zebrafish embryos. CCN1 activated VEGFR2 and downstream MAPK/PI3K signalling pathways, YAP/TAZ, as well as Rho effector mDia1 to enhance tip cell activity and CCN1 itself. VEGFR2 interacted with integrin αvβ3 through CCN1. Integrin αvβ3 inhibitor repressed tip cell number and sprouting in postnatal retinas from endothelial cell-specific Ccn1 transgenic mice, and allograft tumours in Ccn1 transgenic mice showed hyperactive vascular sprouting. Cancer patients with high CCN1 expression have poor survival outcomes and positive correlation with ITGAV and ITGB3 and high YAP/WWTR1. Thus, our data underscore the positive feedback regulation of tip cells by CCN1 through integrin αvβ3/VEGFR2 and increased YAP/TAZ activity, suggesting a promising therapeutic intervention for pathological angiogenesis.
Highlights
Angiogenesis involves extensive remodelling of the extracellular matrix (ECM) and endothelial cells (ECs) (Stupack and Cheresh, 2002)
Tip cells migrate and branch according to increased concentrations of vascular endothelial growth factor (VEGF), whereas exposure to relatively low concentrations of VEGF induces the proliferation of stalk cells
Tip cell specification is initially achieved by DLL4 expression in the topmost cells and by Notch signalling in adjacent ECs
Summary
Angiogenesis involves extensive remodelling of the extracellular matrix (ECM) and endothelial cells (ECs) (Stupack and Cheresh, 2002). The ECM is important for dynamic and multifunctional regulation of cell behaviours and can modulate the bioavailability and activity of growth factors, cytokines, and extracellular enzymes (Aszodi et al, 2006). ECM proteins directly interact with cell surface receptors to activate signal transduction (Bornstein and Sage, 2002). Matricellular proteins are ECM proteins that do not contribute directly to the formation of these structures in vertebrates but are involved in cell–matrix interactions and other diverse cellular functions (Bornstein, 1995). Such proteins include thrombospondin-1, osteonectin, and members of the CYR61/CTGF/NOV (CCN) family of proteins (Lau and Lam, 1999).
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