Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development.

The term ‘vasculogenesis’ refers to the earliest stages of vascular development, during which vascular endothelial cell precursors undergo differentiation, expansion, and coalescence to form a network of primitive tubules (Risau 1997). This initial lattice, consisting purely of endothelial cells that have formed rather homogenously sized interconnected vessels, has been referred to as the primary capillary plexus. The primary plexus is then remodeled by a process referred to as angiogenesis (Risau 1997), which involves the sprouting, branching, and differential growth of blood vessels to form the more mature appearing vascular patterns seen in the adult organism. This latter phase of vascular development also involves the sprouting and penetration of vessels into previously avascular regions of the embryo, and also the differential recruitment of associated supporting cells, such as smooth muscle cells and pericytes, as well as fibroblasts, to different segments of the vasculature (Folkman and D’Amore 1996; Lindahl et al. 1997). The adult vascular network is comprised of large arteries, internally lined by endothelial cells and well ensheathed by smooth muscle cells, that progressively branch into smaller and smaller vessels, terminating in precapillary arterioles that then give rise to capillaries. Capillaries are comprised almost entirely of endothelial cells that are only occasionally coated by a smooth muscle cell-like pericyte. Capillaries then feed into postcapillary venules that progressively associate into larger and larger venous structures; venous structures are fully enveloped by smooth muscle cells, though not to the same degree as arterial structures. The development of a functioning vascular network requires a remarkable degree of coordination between different cell types undergoing complex changes, and is exquisitely dependent upon signals exchanged between these cell types. Vascular endothelial growth factor (VEGF-A) provided the first example of a growth factor specific for the vascular endothelium, and VEGF-A has since been shown to be a critical regulator of endothelial cell development. Not surprisingly, the specificity of VEGF-A for the vascular endothelium results from the restricted distribution of VEGF-A receptors to these cells. The need to regulate the multitude of cellular interactions involved during vascular development suggested that VEGF-A might not be alone as an endothelial cell-specific growth factor. Indeed, there has been a recent explosion in the number of growth factors that specifically act on the vascular endothelium. This explosion involves the VEGF family, which now totals at least five members. In addition, an entirely unrelated family of growth factors, known as the Angiopoietins, recently has been identified as acting via endothelial cell-specific receptors known as the Ties. Most recently, particular members of the very large ephrin family have been identified as having unique roles on endothelium, and at least in some cases appear to act via a receptor that is not only largely restricted to the vascular endothelium but to the endothelium lining venous as opposed to arterial vessels. As we describe in detail below, a variety of studies highlighted by the analyses of knockout mice (as summarized in Table 1) have implicated the VEGFs, the Angiopoietins, and the ephrins as critical players in particular aspects of vascular development.