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.


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.
Tchaikovski
Vadim
V
Department of Cardiology, University Hospital of Maastricht, Cardiovascular Research Institute of Maastricht, P.Debyelaan 25, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
Fellbrich
Guido
G
Waltenberger
Johannes
J
D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology; D006801:Humans; D009000:Monocytes / Q000502:physiology*; D010766:Phosphorylation; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000502:physiology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
C000608036:PGF protein, human; D011257:Pregnancy Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1