TMP-1 promotes VEGF-induced neovascularization in the retina

E. Yamada, T. Tobe, H. Yamada, N. Okamoto, D. J. Zack, Z. Werb, P. D. Soloway, P. A. Campochiaro

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)87-97
Number of pages11
JournalHistology and Histopathology
Volume16
Issue number1
StatePublished - 2001

Keywords

  • Proliferative retinopathies
  • Proteinases
  • Retinal neovascularization
  • TIMP-1
  • VEGF

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology

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