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.

[1]  C. Dabrosin,et al.  Gene transfer of matrix metalloproteinase-9 induces tumor regression of breast cancer in vivo. , 2008, Cancer research.

[2]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[3]  T. Minamoto,et al.  Oncogenic beta-catenin and MMP-7 (matrilysin) cosegregate in late-stage clinical colon cancer. , 2002, Gastroenterology.

[4]  G. Kenter,et al.  Endothelium specific matrilysin (MMP-7) expression in human cancers. , 2007, Matrix biology : journal of the International Society for Matrix Biology.

[5]  B. Rosen,et al.  Role of matrix metalloproteinases in delayed cortical responses after stroke , 2006, Nature Medicine.

[6]  S. Milani,et al.  In situ detection of matrix metalloproteinase-2 (MMP2) and the metalloproteinase inhibitor TIMP2 transcripts in human primary hepatocellular carcinoma and in liver metastasis. , 1997, Journal of hepatology.

[7]  Asif Ahmed,et al.  Release and Complex Formation of Soluble VEGFR-1 from Endothelial Cells and Biological Fluids , 2000, Laboratory Investigation.

[8]  Shigeyoshi Itohara,et al.  Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis , 2000, Nature Cell Biology.

[9]  Z. Werb,et al.  Matrix metalloproteinases in lung: multiple, multifarious, and multifaceted. , 2007, Physiological reviews.

[10]  M. Luisa Iruela-Arispe,et al.  Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors , 2005, The Journal of cell biology.

[11]  P. E. Van den Steen,et al.  Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. , 2000, Blood.

[12]  N. Ferrara,et al.  The biology of VEGF and its receptors , 2003, Nature Medicine.

[13]  Takanori Aoki,et al.  Matrix Metalloproteinases Cleave Connective Tissue Growth Factor and Reactivate Angiogenic Activity of Vascular Endothelial Growth Factor 165* , 2002, The Journal of Biological Chemistry.

[14]  P. Lacal,et al.  Vascular endothelial growth factor receptor-1 is deposited in the extracellular matrix by endothelial cells and is a ligand for theα 5β1 integrin , 2003, Journal of Cell Science.

[15]  M. Shibuya,et al.  The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. , 2005, Clinical science.

[16]  K. Yano,et al.  Matrix Metalloproteinase-7 Facilitates Insulin-Like Growth Factor Bioavailability through Its Proteinase Activity on Insulin-Like Growth Factor Binding Protein 3 , 2004, Cancer Research.

[17]  Hung V. Nguyen,et al.  The Carboxyl-terminal Domain(111165) of Vascular Endothelial Growth Factor Is Critical for Its Mitogenic Potency (*) , 1996, The Journal of Biological Chemistry.

[18]  R. Kendall,et al.  Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Y. Nagashima,et al.  Expression of matrilysin in vascular endothelial cells adjacent to matrilysin‐producing tumors , 1997, International journal of cancer.

[20]  宮本 心一.  Matrix metalloproteinase-7 facilitates insulin-like growth factor bioavailability through its proteinase activity on insulin-like growth factor binding protein-3 , 2004 .

[21]  R. Hebbel,et al.  Binding and displacement of vascular endothelial growth factor (VEGF) by thrombospondin: Effect on human microvascular endothelial cell proliferation and angiogenesis , 2004, Angiogenesis.

[22]  Christopher M. Overall,et al.  Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy , 2006, Nature Reviews Cancer.

[23]  J. Martin Collinson,et al.  Corneal avascularity is due to soluble VEGF receptor-1 , 2006, Nature.

[24]  K. Hirata,et al.  Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human pancreatic adenocarcinomas: clinicopathologic and prognostic significance of matrilysin expression. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  G. Neufeld,et al.  Platelet Factor-4 Inhibits the Mitogenic Activity of VEGF121 and VEGF165 Using Several Concurrent Mechanisms (*) , 1995, The Journal of Biological Chemistry.

[26]  T. Furuya,et al.  Prognostic Significance of Matrix Metalloproteinase‐7 (MMP‐7) Expression at the Invasive Front in Gastric Carcinoma , 2002, Japanese journal of cancer research : Gann.

[27]  T. Libermann,et al.  Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia , 2003 .

[28]  J. Raffetto,et al.  Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. , 2008, Biochemical pharmacology.

[29]  Taiji Ito,et al.  The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells , 2007, Oncogene.

[30]  居軒 功.  Connective tissue growth factor binds vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis , 2004 .

[31]  R. Kendall,et al.  Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. , 1996, Biochemical and biophysical research communications.

[32]  I. Bernard-Pierrot,et al.  Heparin affin regulatory peptide binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis , 2004, Oncogene.

[33]  M. Iruela-Arispe,et al.  ADAMTS1/METH1 Inhibits Endothelial Cell Proliferation by Direct Binding and Sequestration of VEGF165* , 2003, Journal of Biological Chemistry.

[34]  C. Brinckerhoff,et al.  Matrix metalloproteinases: role in arthritis. , 2006, Frontiers in bioscience : a journal and virtual library.

[35]  M. Fini,et al.  MMPs in the eye: emerging roles for matrix metalloproteinases in ocular physiology , 2002, Progress in Retinal and Eye Research.

[36]  M. Moses,et al.  Making the cut: protease-mediated regulation of angiogenesis. , 2006, Experimental cell research.

[37]  T. Takada,et al.  A high peripheral microvessel density count correlates with a poor prognosis in pancreatic cancer , 2005, Journal of Gastroenterology.

[38]  A. N. Corps,et al.  A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation. , 1998, Biology of reproduction.

[39]  K. Osteen,et al.  The matrix metalloproteinase system: changes, regulation, and impact throughout the ovarian and uterine reproductive cycle. , 2003, Endocrine reviews.

[40]  W. Jelkmann,et al.  Pitfalls in the measurement of circulating vascular endothelial growth factor. , 2001, Clinical chemistry.

[41]  A. Ochiai,et al.  Matrix metalloproteinase-7 degrades all insulin-like growth factor binding proteins and facilitates insulin-like growth factor bioavailability. , 2005, Biochemical and biophysical research communications.

[42]  P. V. van Diest,et al.  Relationships between vascularization and proliferation in invasive breast cancer , 1999, The Journal of pathology.

[43]  Kenji Nakamura,et al.  Crosstalk between neovessels and mural cells directs the site-specific expression of MT1-MMP to endothelial tip cells , 2007, Journal of Cell Science.

[44]  C. Overall,et al.  Identification of Candidate Angiogenic Inhibitors Processed by Matrix Metalloproteinase 2 (MMP-2) in Cell-Based Proteomic Screens: Disruption of Vascular Endothelial Growth Factor (VEGF)/Heparin Affin Regulatory Peptide (Pleiotrophin) and VEGF/Connective Tissue Growth Factor Angiogenic Inhibitory Co , 2007, Molecular and Cellular Biology.

[45]  Christopher M Overall,et al.  Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. , 2006, Nature reviews. Cancer.

[46]  C. Libert,et al.  Matrilysin (matrix metalloproteinase-7): a new promising drug target in cancer and inflammation? , 2004, Cytokine & growth factor reviews.

[47]  L. Matrisian,et al.  Matrix Metalloproteinases as Mediators of Reproductive Function , 2022 .