TMP-1 promotes VEGF-induced neovascularization in the retina

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

Research output: Contribution to journalArticle

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

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Thymidine Monophosphate
Tissue Inhibitor of Metalloproteinase-1
Vascular Endothelial Growth Factor A
Retina
Retinal Neovascularization
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinases
Transgenes
Tissue Inhibitor of Metalloproteinases
Chorioallantoic Membrane
Basement Membrane
Transgenic Mice
Proteolysis
Cell Movement
Extracellular Matrix
Blood Vessels
Electron Microscopy
Endothelial Cells
Cell Proliferation
Light

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Anatomy
  • Histology
  • Pathology and Forensic Medicine

Cite this

TMP-1 promotes VEGF-induced neovascularization in the retina. / Yamada, E.; Tobe, T.; Yamada, H.; Okamoto, N.; Zack, Donald J; Werb, Z.; Soloway, P. D.; Campochiaro, Peter A.

In: Histology and Histopathology, Vol. 16, No. 1, 2001, p. 87-97.

Research output: Contribution to journalArticle

Yamada, E, Tobe, T, Yamada, H, Okamoto, N, Zack, DJ, Werb, Z, Soloway, PD & Campochiaro, PA 2001, 'TMP-1 promotes VEGF-induced neovascularization in the retina', Histology and Histopathology, vol. 16, no. 1, pp. 87-97.
Yamada E, Tobe T, Yamada H, Okamoto N, Zack DJ, Werb Z et al. TMP-1 promotes VEGF-induced neovascularization in the retina. Histology and Histopathology. 2001;16(1):87-97.
Yamada, E. ; Tobe, T. ; Yamada, H. ; Okamoto, N. ; Zack, Donald J ; Werb, Z. ; Soloway, P. D. ; Campochiaro, Peter A. / TMP-1 promotes VEGF-induced neovascularization in the retina. In: Histology and Histopathology. 2001 ; Vol. 16, No. 1. pp. 87-97.
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