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1 From the Division of Ophthalmology and the 2 Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico; and 3 Veterans Administration Medical Center, Albuquerque, New Mexico.
PURPOSE. Hypoxia and growth factors are postulated to be involved in the
development of retinal neovascularization through the regulation of
extracellular proteinase production. It has been shown that matrix
metalloproteinases (MMPs) are elevated in the retina during the
neovascularization process. However, the factors and mechanisms that
regulate the expression of these enzymes are not well characterized.
The present study examines the potential role of tumor necrosis factor
(TNF)-
as a regulator of MMPs in the retinal neovascularization
process.
METHODS. C57/Bl6 mice were treated with 75% oxygen (experimental) or room air
(control) from postnatal days (P)7 through P12, followed by room air
until P17. Retinas were collected at P13, P15, or P17 and total RNA
analyzed for the relative level of TNF, TNF receptor (p55), and
TNF-converting enzyme (TACE). Immunostaining was used to identify
changes in TNF protein expression as well as to localize TNF within
specific retinal cell types. The role of TNF in stimulating retinal
microvascular endothelial cell (RMVEC) proteinase production was
evaluated using isolated murine RMVECs grown in normoxic or hypoxic
conditions. Message expression was analyzed by RT-PCR and protein
expression by zymographic analysis.
RESULTS. TNF mRNA was increased in the retinas of experimental animals on P13
and P15, during the early stages of retinal neovascularization. In
addition to being expressed by Müller glial cells and the inner
nuclear layer, additional expression was noted in the outer nuclear
layer of experimental animals. No significant level of apoptosis was
detected in the retina of experimental animals with retinal
neovascularization. Isolated RMVECs did not significantly increase MMP
production directly in response to a hypoxic stimulus, but required the
presence of exogenous TNF. TNF increased the expression of
MT1-MMP, MMP-3, and MMP-9 in these cells. The levels of TACE and p55,
proteins important in mediating the response of cells to TNF, were
found to be increased by the angiogenic protein, vascular endothelial
growth factor (VEGF), which was also elevated in the experimental
retinas.
CONCLUSIONS. TNF levels increase in experimental mouse retinas exposed to hypoxic
stimuli. Increased production of MMPs by RMVECs does not occur directly
in response to a hypoxic stimulus. These cells are responsive, however,
to stimulation by TNF, which enhances the production of specific
members of the MMP family. VEGF also plays a role in this process
through its regulation of TACE and p55 mRNA in the vascular endothelial
cells. These findings support the hypothesis that these two growth
factors have a role in the regulation of extracellular proteinase
expression during retinal neovascularization.
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