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Increased neovascularization in mice lacking tissue inhibitor of metalloproteinases-3
Quteba Ebrahem1, Jian Hua Qi, Masahiko Sugimoto
1Department of Ophthalmology, Cole Eye Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio 44195, USA.
Purpose:
Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a matrix-bound inhibitor of matrix metalloproteinases (MMPs). The authors have previously determined a novel function of TIMP-3 to inhibit vascular endothelial growth factor (VEGF)-mediated angiogenesis. Here, the authors examined the in vivo angiogenic phenotype of ocular vessels in mice deficient in TIMP-3.
Methods:
VEGF-mediated corneal neovascularization and laser-induced choroidal neovascularization (CNV) were examined in TIMP-3-null mice. The effects of the absence of TIMP-3 on the phosphorylation status of the VEGF-receptor-2 (VEGFR-2) and the downstream signaling pathways were evaluated biochemically. In addition, the activation state of MMPs in the retina of TIMP-3-deficient mice was examined by in situ zymography.
Results:
The results of these studies determine an accentuation of pathologic VEGF-mediated angiogenesis in the cornea and laser-induced CNV in mice lacking TIMP-3. In the absence of the MMP inhibitor, pathophysiological changes were observed in the choroidal vasculature concomitantly with an increase in gelatinolytic activity. These results suggest that an imbalance of extracellular matrix homeostasis, together with a loss of an angiogenesis inhibitor, can prime vascular beds to be more responsive to an angiogenic stimulus.
Conclusions:
In light of the recent studies suggesting that genetic variants near TIMP-3 influence susceptibility to age-related macular degeneration, these results imply that TIMP-3 may regulate the development of the choroidal vasculature and is a likely contributor to increased susceptibility to choroidal neovascularization.
Insights
Mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3) showed increased pathological blood vessel growth in the eye. This suggests TIMP-3 is crucial for regulating ocular neovascularization and may impact age-related macular degeneration.
Area of Science:
- Ophthalmology
- Molecular Biology
- Genetics
Background:
- Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a known inhibitor of matrix metalloproteinases (MMPs).
- TIMP-3 has a newly identified role in inhibiting vascular endothelial growth factor (VEGF)-mediated angiogenesis.
- The study investigates the in vivo function of TIMP-3 in ocular neovascularization.
Purpose of the Study:
- To examine the in vivo angiogenic phenotype of ocular vessels in mice lacking TIMP-3.
- To understand the role of TIMP-3 in VEGF-mediated angiogenesis in the eye.
- To explore the implications of TIMP-3 deficiency in ocular vascular diseases.
Main Methods:
- Assessed VEGF-mediated corneal neovascularization and laser-induced choroidal neovascularization (CNV) in TIMP-3-null mice.
- Biochemically evaluated the impact of TIMP-3 absence on VEGF-receptor-2 (VEGFR-2) phosphorylation and downstream signaling.
- Utilized in situ zymography to examine MMP activation in the retinas of TIMP-3-deficient mice.
Main Results:
- Mice lacking TIMP-3 exhibited exacerbated pathological angiogenesis in the cornea and laser-induced CNV.
- Absence of TIMP-3 led to pathophysiological changes in choroidal vasculature and increased gelatinolytic activity.
- These findings indicate that disrupted extracellular matrix homeostasis and loss of TIMP-3 prime vascular beds for heightened angiogenic response.
Conclusions:
- TIMP-3 deficiency accentuates pathological angiogenesis, particularly in the choroid.
- TIMP-3 plays a regulatory role in choroidal vasculature development.
- TIMP-3 is implicated as a potential factor in susceptibility to choroidal neovascularization and age-related macular degeneration.
