TIMP-1 promotes VEGF-induced neovascularization in the retina.

Abstract

Proteolysis of vascular basement membranes and surrounding extracellular matrix is a critical early step in neovascularization. It requires alteration of the balance between matrix metalloproteinases (MMPs) and proteins that bind to and inactivate MMPs, tissue inhibitors of metalloproteinases (TIMPs). TIMP-1 has been demonstrated to inhibit neovascularization in chick chorioallantoic membranes. However, TIMP-1 has also been shown to either promote or inhibit cell proliferation and migration in different settings. To determine whether genetic alteration of the MMP/TIMP-1 ratio would alter retinal neovascularization, we crossed mice that express vascular endothelial growth factor (VEGF) in photoreceptors with TIMP-1-deficient mice or mice that overexpress TIMP-1. Compared to VEGF transgene-positive/TIMP-1-sufficient mice, VEGF transgene-positive/TIMP-1-deficient mice showed smaller neovascular lesions. There was also no difference between the two groups of mice in the appearance of the neovascularization by light or electron microscopy. Compound VEGF/TIMP-1 transgenic mice had increased expression of both VEGF and TIMP-1 in the retina, and had more neovascularization than mice that had increased expression of VEGF alone. These gain- and loss-of-function data suggest that alteration of the TIMP-1/MMP ratio modulates retinal neovascularization in a complex manner and not simply by altering the proteolytic activity and thereby invasiveness of endothelial cells.

• Authors: E Yamada, T Tobe, H Yamada, N Okamoto, D J Zack, Z Werb, P D Soloway, P A Campochiaro
• Journal: Histology and histopathology (Histol Histopathol) Vol. 16 Issue 1 Pg. 87-97 (01 2001) ISSN: 0213-3911 [Print] Spain
• PMID: 11193216 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Actins
• Endothelial Growth Factors
• Lymphokines
• Tissue Inhibitor of Metalloproteinase-1
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors

Topics

• Actins (biosynthesis, genetics)
• Animals
• Blotting, Northern
• Blotting, Southern
• Drug Synergism
• Endothelial Growth Factors (pharmacology)
• Lymphokines (pharmacology)
• Mice
• Mice, Transgenic
• Microscopy, Electron
• Neovascularization, Physiologic (drug effects, genetics)
• Retinal Vessels (drug effects, pathology)
• Reverse Transcriptase Polymerase Chain Reaction
• Tissue Inhibitor of Metalloproteinase-1 (deficiency, genetics, physiology)
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors