TIMP-1 promotes VEGF-induced neovascularization in the retina.
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.
Yamada
E
E
The Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-9277, USA.
Tobe
T
T
Yamada
H
H
Okamoto
N
N
Zack
D J
DJ
Werb
Z
Z
Soloway
P D
PD
Campochiaro
P A
PA
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D004357:Drug Synergism; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D008222:Lymphokines / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics; D012171:Retinal Vessels / Q000187:drug effects* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000199:Actins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D019715:Tissue Inhibitor of Metalloproteinase-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors