Degradation of soluble VEGF receptor-1 by MMP-7 allows VEGF access to endothelial cells.
Vascular endothelial growth factor (VEGF) signaling in endothelial cells serves a critical role in physiologic and pathologic angiogenesis. Endothelial cells secrete soluble VEGF receptor-1 (sVEGFR-1/sFlt-1), an endogenous VEGF inhibitor that sequesters VEGF and blocks its access to VEGF receptors. This raises the question of how VEGF passes through this endogenous VEGF trap to reach its membrane receptors on endothelial cells, a step required for VEGF-driven angiogenesis. Here, we show that matrix metalloproteinase-7 (MMP-7) degrades human sVEGFR-1, which increases VEGF bioavailability around the endothelial cells. Using a tube formation assay, migration assay, and coimmunoprecipitation assay with human umbilical vein endothelial cells (HUVECs), we show that the degradation of sVEGFR-1 by MMP-7 liberates the VEGF(165) isoform from sVEGFR-1. The presence of MMP-7 abrogates the inhibitory effect of sVEGFR-1 on VEGF-induced phosphorylation of VEGF receptor-2 on HUVECs. These data suggest that VEGF escapes the sequestration by endothelial sVEGFR-1 and promotes angiogenesis in the presence of MMP-7.
Ito
Ta-Kashi
TK
Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
Ishii
Genichiro
G
Saito
Seiji
S
Yano
Keiichi
K
Hoshino
Ayuko
A
Suzuki
Tasuku
T
Ochiai
Atsushi
A
D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D020783:Matrix Metalloproteinase 7