Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1

Abstract

Treatment of human monocytes with vascular endothelial growth factor (VEGF) isolated from tumor cell supernatants was reported to induce monocyte activation and migration. In this study we show that recombinant human VEGF165, and VEGF121 had a maximal effect on human monocyte migration at 65 to 250 pmol/L. Chemotactic activity of VEGF165 was inhibited by a specific antiserum against VEGF, by heat treatment of VEGF165, and by protein kinase inhibitors. In addition, we could show that VEGF-stimulated monocyte migration is mediated by a pertussis toxin-sensitive GTP-binding protein. Placenta growth factor (PlGF152), a heparin-binding growth factor related to VEGF, was also chemotactic for monocytes at concentrations between 2.5 and 25 pmol/L. In accordance with these findings, human monocytes showed specific and saturable binding for 125I-VEGF165 (half-maximal binding at 1 to 1.5 nmol/L). Using Northern blot analysis, we further could show that human monocytes express only the gene for the VEGF receptor type, flt-1, but not for the second known VEGF receptor, KDR. Resting monocytes expressed low levels of flt-1 gene only. Brief exposure (2 to 4 hours) of human monocytes to lipopolysaccharide, a prototypic monocyte activator, led to a significant upregulation of the flt-1 mRNA level. The results presented here suggest that monocyte chemotaxis in response to VEGF and most likely to PlGF152 is mediated by flt-1 and thus show a possible function for the VEGF-receptor flt-1.

Stromal cell‐derived factor 1α (SDF‐1α) induces gene‐expression of early growth response‐1 (Egr‐1) and VEGF in human arterial endothelial cells and enhances VEGF induced cell proliferation

“…VEGF mainly acts via its receptors KDR and Flt-1. While KDR seems to be the receptor which is responsible for the angiogenetic potency of VEGF, Flt-1, in addition to other functions, mediates VEGF-induced migration in human monocytes and macrophages (Barleon et al 1996;Hiratsuka et al 1998;Neufeld et al 1999;Hiratsuka et al 2001). At that time the significance of the SDF induced expression of Egr-1 and VEGF as well as its function in endothelial cells remains unclear, but further studies focusing on this point seem to be reasonable.…”

Anti‐vascular endothelial growth factor receptor‐2 (Flk‐1/KDR) antibody suppresses contact hypersensitivity

“…On the other hand, VEGFR-1 has also been implicated in cell recruitment. VEGF is able to stimulate monocyte/macrophage migration through endothelial monolayers using VEGFR-1 signaling (63). Recently, VEGFR-1's importance was again recognized when Luttun et al (64) reported anti-VEGFR-1 antibody inhibited angiogenesis in tumors and inflammatory disorders.…”

Blood–retinal barrier breakdown in experimental coronavirus retinopathy: association with viral antigen, inflammation, and VEGF in sensitive and resistant strains

“…VEGF receptors have been identified on monocytes ŽShen et al, 1993; Barleon et al, 1996;Clauss et al, 1996; . Sawano et al, 2001 and VEGF can stimulate the activa-Ž tion and migration of monocytes Clauss et al, 1990Clauss et al, , .…”

“…Sawano et al, 2001 and VEGF can stimulate the activa-Ž tion and migration of monocytes Clauss et al, 1990Clauss et al, , . 1996Barleon et al, 1996;Heil et al, 2000 . However, despite the fact that monocytes are the primary infiltrating cell type, VEGF does not appear to promote monocyte Ž .…”

“…Vascular endothelial growth factor VEGF is well characterized as an angiogenic agent and a vascular perme-Ž ability factor Senger et al, 1983Senger et al, , 1986Roberts and . Palade, 1995;Dvorak et al, 1995;Ozaki et al, 1997 , but recent findings show that it is also involved with the recruitment and activation of inflammatory cells and their Ž adhesion to the vascular endothelium Barleon et al, 1996; . Clauss et al, 1996;Melder et al, 1996;Lu et al, 1999 .…”