TIMP-1 promotes VEGF-induced neovascularization in the retina

Proteolysis of vascular basement membranes and surrounding extracellular ma trix 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 chor ioallantoic membranes. However, TIMP-1 has also been shown to either promot e or inhibit cell proliferation and migration in different settings. To det ermine whether genetic alteration of the MMP/TIMP-1 ratio would alter retin al neovascularization, we crossed mice that express vascular endothelial gr owth factor (VEGF) in photoreceptors with TIMP-1-deficient mice or mice tha t overexpress TIMP-1. Compared to VEGF transgene-positive/TIMP-1-sufficient mice, VEGF transgene-positive/TIMP-1-deficient mice showed smaller neovasc ular lesions. There was also no difference between the two groups of mice i n 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 h ad increased expression of VEGF alone. These gain- and loss-of-function dat a suggest that alteration of the TIMP-1/MMP ratio modulates retinal neovasc ularization in a complex manner and not simply by altering the proteolytic activity and thereby invasiveness of endothelial cells.