TIMP-1 promotes VEGF-induced neovascularization in the retina

E. Yamada1,2*, T. Tobe1,2*, H. Yamada1,2*, N. Okamoto1,2, D.J. Zack1,2,3, Z. Werb4, P.D. Soloway5 and P.A. Campochiaro1,2

The Departments of 1Ophthalmology, 2 Neuroscience, and 3Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 4Department of Anatomy, Laboratory of Radiobiology and Environmental Health, University of California, San Francisco, CA and 5Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA

* contritubed equally to the manuscript

Offprint requests to: Peter A. Campochiaro M.D., Maumenee 719, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287-9277. USA. Fax: (410) 614-9315. e-mail: pcampo@jhmi.edu

Summary. 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. Histol. Histopathol. 16, 87-97 (2001)

Key words: TIMP-1, VEGF, retinal neovascularization, proteinases, proliferative retinopathies

DOI: 10.14670/HH-16.87