Role of the ephrin and Eph receptor tyrosine kinase families in angiogenesis and development of the cardiovascular system

Abstract

Angiogenesis is a highly complex orchestrated process that plays a critical role in normal development and in the pathophysiology of multiple disease processes, including tumour neovascularization, ischaemic recovery, and wound healing. In recent years there has been a resurgence of interest in Eph receptors and their ligands, ephrins, as their participation in vasculogenesis and angiogenesis has become apparent. The Eph receptor family is the largest family of receptor tyrosine kinases identified to date. The Eph receptors and their membrane-anchored ligands, ephrins, are unique in that they mediate bi-directional signalling. This is concomitant with activation of the Eph receptor tyrosine kinase domain and transduction of the typical forward signal into the receptor-bearing cell. The ligand-receptor interaction also leads to transduction of a reverse signal into the ephrin-bearing cell. The Eph/ephrin signalling mechanism is responsible for diverse and complex biological functions mediated by Eph receptors and ephrin ligands. These include vascular development, tissue-border formation, cell migration, axon guidance, and synaptic plasticity. The role of Eph receptors and ephrins in the processes of development of the cardiovascular system, angiogenesis, and vascular remodelling has been the subject of intense investigation since they were first identified in 1987. This review addresses the role of this new growth factor receptor tyrosine kinase family in those processes and provides new insights into the way in which Eph receptors and ephrin ligands modulate the angiogenic response and participate in vascular remodelling and vascular boundary formation during development of the cardiovascular system and vascularization of cancer.