Publication: TIMP-1 promotes VEGF-induced neovascularization in the retina
Authors
Yamada, E. ; Tobe, T. ; Yamada, H. ; Okamoto, N. ; Zack, D.J. ; Werb, Z. ; Soloway, P.D. ; Campochiaro, P.A.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
Proteolysis of vascular basement membranes
and surrounding extracellular matrix is a critica1 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 MMPDIMP-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 transgenepositive/
TIMP-1-sufficient mice, VEGF transgenepositive1TIMP-
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 VEGFITIMP-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 gainand
loss-of-function data suggest that alteration of the
TIMP-1MMP ratio modulates retinal neovascularization
in a complex manner and not simply by altering the proteolytic activity and thereby invasiveness of
endothelial cells.
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