VEGF receptor switching in heart development and disease

Abstract

Vascular endothelial growth factor (VEGF), also known as VEGF-A to distinguish it from other isoforms (B–D) that are mainly involved in lymphangiogenesis, is an endothelial cell mitogen that has an essential role in both vasculogenesis and angiogenesis.1 VEGF regulates the development of endoderm-derived tissues, such as the vascular endothelium and the endocardium, by inducing multiple angiogenic cellular responses, including promotion of survival, migration, and differentiation, through the activation of Akt signalling in endothelial cells.2 VEGF exerts its biological actions by interacting with two main tyrosine kinase receptors, known as VEGFR-1 \[or FMS-like tyrosine kinase-1 (Flt-1)] and VEGFR-2 [alternative names: foetal liver kinase-1 and kinase insert domain receptor (KDR)\] ( Figure 1 ).3 Figure 1 A schematic representation of the cardiomyocyte VEGF signalling pathway. Flt-1 and KDR are the two major VEGF receptors. In cardiomyocytes, VEGF drives cardiac hypertrophy or its regression, depending on the prevalent binding to KDR or Flt-1, respectively. Copper (Cu) supplementation determines a switch in the VEGF signalling pathway, increasing the ratio of Flt-1 to KDR. By this mechanism, copper induces regression of cardiomyocyte hypertrophy. VEGF, vascular endothelial growth factor; Flt-1, FMS-like tyrosine kinase-1; KDR, kinase insert domain receptor; PKG-1, cGMP-dependent protein kinase-1; Cu, copper; DAG, diacylglycerol; IP3, inositol trisphosphate; Sos, Son of Sevenless; Shc, Src-homology collagen protein; Grb-2, growth factor receptor-bound protein 2; MEK1/2, mitogen activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) kinase 1/2; PKC, protein kinase C; PLC-γ, phospholipase C-γ; PD98059 (PD) and UO126 are selective ERK1/2 inhibitors. Intriguingly, based on work … *Corresponding author. Tel: +39 0871 41512; fax: +39 0871 402817. E-mail address : rdecater{at}ifc.cnr.it