Dissection of Monocyte and Endothelial Activities by Using VEGF-Receptor Specific Ligands

Abstract

Vascular endothelial growth factor (VEGF) is the major inducer of angiogenesis and vasculogenesis (Risau, 1997). It was isolated based on its ability to induce proliferation of endothelial cells but not fibroblasts (Leung et al., 1989). Based on this competency VEGF emerged as a highly good candidate as an angiogenesis-specific factor. Because VEGF is produced in response to hypoxia it describes a physiological mean to ablate the need of nutrients and oxygen by the induction of new blood vessels. In vitro, it induces several activities in endothelial cells, which are believed to be associated with angiogenesis, such as proliferation, survival and migration. But it also displays activities in endothelial cells, which were different from what was expected from an endothelial cell specific mitogen. VEGF can also induce vascular hyperpermeability, leading to its original description as vascular permeability factor (VPF) and turned out to be an inducer of tissue factor, the initiator of blood coagulation (Nemerson, 1988). In addition it is able to increase both the plasminogen activator and its inhibitor (Pepper et al., 1991). VEGF was found to cause release of von Willebrand factor from the Weibel-Palade bodies in endothelial cells and to increase the surface expression of P-selectin, two processes which comprise possible links to blood coagulation and inflammation, respectively. In consequence, the question arose whether VEGF would be a jack of all trades, comparable to another unspecific growth factor, fibroblast growth factor (FGF) (Clauss and Schaper, 2000). This point of view was enforced by the early finding that VEGF not only acts on endothelial cells but also on other cells. In this context monocytes were identified shortly after the discovery of VEGF as vascular endothelial growth factor (Clauss et al., 1990). In monocytes, VEGF induces chemotaxis, transmigration through endothelial monolayers, tissue factor and the inducible NO-Synthetase (Clauss, 1998). Furthermore, it was found to inhibit the differentiation to dendritic cells and to enforce the transition to endothelial cells (Gabrilovich et al., 1998). These diverse activities are not necessarily associated with angiogenesis. It should therefore be important to understand the mechanism of VEGF-elicited activities and, if possible to be able to distinguish VEGF-mediated activities on endothelial cells from those onto monocytes.