Inhibition of VEGF-R2-mediated signalling cascade by endogenous antagonists. Inhibition of VEGF-R2-mediated signalling cascade by endogenous antagonists. (A) Perlecan, an extracellular matrix component, is composed of several functional domains. The C-terminal domain, also named V domain or endorepellin, is released from the full length protein by proteolytic processing by cathepsin-L. (B) Endorepellin contains three laminin G domains (LG1, LG2 and LG3) separated by EGF domains. Metalloproteinases such as BMP-1 cleave endorepellin to release the LG3 domain from the LG1-LG2 fragment. (C) The LG1-LG2 fragment of endorepellin binds to VEGF-R2 inhibiting its downstream phosphorylation. LG3 binds to the α2 domain of the α2β1 integrin which can also inhibit VEGF-R2 activation through SHP-1. Inhibition of VEGF-R2 signalling enables PDGF-Rβ-mediated signalling. BMP-1, bone morphogenetic protein-1; EGF, endothelial growth factor; PDGF-BB, platelet derived growth factor b; PDGF-Rβ, platelet-derived growth factor receptor β; SHIP-1, SH2 domain-containing inositol-5’-phosphatase 1; VEGF-A, vascular endothelial growth factor a; VEGF-R2, vascular endothelial growth factor receptor 2. Adapted from Zoeller et al.94 Huajun Zhang et al. Open Heart 2014;1:e000016 ©2014 by British Cardiovascular Society