Vascular Endothelial Growth Factor Upregulates the Expression of Matrix Metalloproteinases in Vascular Smooth Muscle Cells

Abstract

Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis that stimulates proliferation, migration, and proteolytic activity of endothelial cells. Although the mitogenic activity of VEGF is endothelial cell specific, recent reports indicate VEGF is able to stimulate chemotaxis and tissue factor production in monocytes. VEGF-stimulated activity in monocytes is mediated by the VEGF receptor flt-1. The purpose of the present study was to investigate the effects of VEGF on another major cell type in the vascular wall, namely, the vascular smooth muscle cell (SMC). Using cultured cells, we showed that VEGF has a minimal mitogenic effect on SMCs, which is in accordance with published data. However, VEGF treatment significantly enhanced production of matrix metalloproteinase (MMP)-1, -3, and -9 by human SMCs. The upregulation of MMP-1 and MMP-9 was pronounced, and the stimulation for MMP-3 was less prominent. Stimulation could be demonstrated at both protein and mRNA levels, as reflected by ELISA, zymography, and Northern blot analysis. To explore the signal transduction pathway for the effect of VEGF on SMCs, we studied the expression of 2 high-affinity VEGF receptors, the kinase insert domain-containing receptor (KDR) and flt-1, in human SMCs. Both reverse transcriptase-polymerase chain reaction and immunoblotting revealed the expression of flt-1. Immunoprecipitation followed by immunoblotting illustrated phosphorylation of the flt-1 receptor after VEGF treatment. Similar methodology failed to detect expression of KDR in human SMCs. These data suggest the role of flt-1 in mediating VEGF-stimulated MMP expression of SMCs. The physiological relevance of MMP upregulation was studied by examining VEGF-stimulated SMC migration through 2 synthetic extracellular matrix barriers, Matrigel and Vitrogen. Our results indicate that VEGF treatment accelerated SMC migration through both barriers, and that this response was blocked by MMP inhibition in Matrigel, which supports a permissive role of MMP in SMC migration. These data are the first to show a direct effect of VEGF on SMCs. SMC-derived MMPs may be an additional source of proteases to digest vascular basement membrane, which is a crucial step in the initial stage of angiogenesis. The MMPs may also contribute to SMC migration in angiogenesis and atherogenesis.

Partial persistence of exercise-induced myocardial angiogenesis following 4-week detraining in the rat

“…ANOVA yielded P = <0.0001 for all except bFGF (NS). * and # indicate P < 0.05 (Tukey post-test) versus control and trained, respectively (Wang and Keiser 1998). The role of VEGF in relation to the exercise-induced modiWcations of skeletal muscles, the mode of capillary growth (by intussusceptions rather than sprouting) and the mechanical forces involved have been thoroughly discussed by Brown and Hudlicka (2003).…”

Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2

“…9 Activation of VEGFR-1 by VEGF in endothelial cells lacking VEGFR-2 does not induce cell proliferation. 9 VEGFR-1 plays an important role in modulating the activities of VEGFR-2 37,38 and the circulating levels of VEGF, in regulating extracellular matrix proteolytic activity, 39 and in controlling the release of nitric oxide by endothelial cells. 9 These aspects are mainly due to the different signal transduction cascades induced by VEGFR-1 and VEGFR-2; and specifically, for cell proliferation, to the activation of mitogen-activated protein kinase (MAPK) only by VEGFR-2.…”

Effects of geldanamycin on HIF-1α mediated angiogenesis and invasion in prostate cancer cells

“…16,[38][39][40] Our results indicated that in DU-145 cells MMP-9 and MMP2 levels did not change upon incubation in hypoxia or with the addition of GA to hypoxic-treated cells 18 used breast cancer cells to demonstrate in certain hypoxic cell lines in fact lead to increased MMP-9 but not MMP-2 levels. However, they kept their cells in hypoxia for 24 h. Other studies have demonstrated that VEGF can upregulate MMP-9 via its activation of VEGF receptors in different cell lines.…”