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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:322.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

The Molecular Basis of VEGFR-1 Signal Transduction Pathways in Primary Human Monocytes

Vadim Tchaikovski; Guido Fellbrich; Johannes Waltenberger

From the Department of Cardiology, University Hospital of Maastricht, and Cardiovascular Research Institute of Maastricht (CARIM), Maastricht, the Netherlands.

Correspondence to Johannes Waltenberger, MD, PhD, Department of Cardiology, University Hospital of Maastricht, Cardiovascular Research Institute of Maastricht (CARIM), P.Debyelaan 25, P.O. Box 5800, 6202 AZ Maastricht, the Netherlands. E-mail j.waltenberger{at}cardio.azm.nl

Abstract

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.

Arteriogenesis and wound healing are largely monocyte- and VEGFR1-dependent. VEGFR-1 intracellular signaling pathways were identified and characterized in primary human monocytes. PI-3K appears to be a central regulator in VEGFR-1 signaling mediating the activation of Akt, p38, and ERK1/2. These pathways are critically involved in VEGFR-1–dependent primary monocyte chemotaxis.

Key Words: monocytes • arteriogenesis • coronary collaterals • VEGFR • growth factors • signal transduction