The molecular basis of VEGFR-1 signal transduction pathways in primary human monocytes.

OBJECTIVE Arteriogenesis, the growth of preexisting arterioles into functional arteries, is dependent on the proper function of monocytes. Likewise, wound healing is monocyte-dependent. The activation of vascular endothelial growth factor receptor-1 (VEGFR-1) in monocytes induces a chemotactic response, triggers the expression of tissue factor, and gene expression of cytokines and chemokines. Little is known about intracellular signaling pathways mediating the biological functions triggered by VEGFR-1 in primary monocytes. METHODS AND RESULTS Monocytes were isolated from peripheral venous blood of young healthy individuals using indirect magnetic labeling. Stimulation of monocytes with either vascular endothelial growth factor-A (VEGF-A) or placenta growth factor (PlGF-1) triggered VEGFR-1 autophosphorylation and phosphorylation of distinct downstream proteins: phosphatidylinositol-3 kinase (PI-3K), Akt, p38, and extracellular signal-regulated kinase-1/2 (ERK1/2). PI-3K appears to be a central regulator in VEGFR-1 signaling in monocytes as the activation of Akt, p38, and ERK1/2 are PI-3-K-dependent. In addition, Akt activation functions downstream of p38 kinase. VEGFR-1-mediated chemotaxis of monocytes is dependent on the activation of PI-3K, p38 kinase, Akt, and ERK1/2, when assessed in a modified Boyden chamber. CONCLUSIONS Both PlGF-1 and VEGF-A can activate VEGFR-1-dependent signaling pathways in primary human monocytes, leading to the activation of several intracellular signaling pathways. These pathways are critically involved in primary monocyte chemotaxis.