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Yiwen Li, Deqiang Huang, Xin Xia, Zhengying Wang, Lingyu Luo, Rong Wen; What Is The Role Of Ccr3 In Choroidal Neovascularization?. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1011.
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The exudative or wet age-related macular degeneration (AMD) with choroidal neovascularization (CNV) could result in rapid and severe loss of vision. Vascular endothelial growth factor A (VEGF-A) plays a critical role in CNV development. Recently, the eosinophil/mast cell chemokine receptor CCR3 was reported to also have a critical role in CNV development and CCR3 targeting was reported to be superior to VEGF-A neutralization to suppress CNV. We examined the role of CCR3 in CNV development in the subretinal Matrigel model in both rat and mouse.
CNV was induced in adult Sprague Dawley rats and BALB/c mice by subretinal injection of Matrigel trans-scleraly. CCR3 specific antagonist SB328437, CCR3 neutralizing antibodies (CCR3 ab) (clone 83103, R & D Systems), VEGF neutralizing antibodies (VEGF ab) (R & D Systems), or rapamycin was dissolved in phosphate buffered saline (PBS) or dimethyl sulfoxide then PBS, and mixed with Matrigel immediately before injection. CNV was allowed to develop for 12 days. Animals were killed and perfused with a DiI solution to stain blood vessels. Eyes were embedded in 5% agarose. Serial sections were cut on a vibratome to cover the entire Matrigel area and examined by confocol microscopy. CNV area was calculated and analyzed.
In both rat and mouse, extensive CNV was found in the Matrigel injected area in the control group, as well as in groups treated with SB328437 or CCR3-ab. Quantitative analyses showed no statistic difference in CNV areas between the control eyes and eyes treated with SB328437 or CCR3-ab. In contrast, the CNV areas in eyes treated with VEGF-ab or rapamycin in rat are significantly smaller than in the control eyes as well as in the eyes treated with CCR3-ab or SB328437. Rapamycin treatment also inhibited CNV significantly in mouse. In fact, CNV was completely absent in 10 out of 14 eyes in the VEGF-ab group and 13 out of 16 eyes in the rapamycin group in rat, and 9 out of 10 in the rapamycin treated group in mouse.
Our results show that CCR3 targeting either with CCR3 neutralizing antibodies or CCR3 specific antagonist SB328437 has no inhibitory effect on CNV development in the Matrigel model of CNV in rat and mouse. These results argue against a role of CCR3 in CNV development and raise a question as to whether CCR3 is a valid therapeutic target for CNV. In contrast, our experiments confirmed the critical role of VEGF-A in CNV development and that VEGF-A targeting is an effective approach to suppress CNV. In addition, rapamycin, an inhibitor of mTOR (mammalian target of rapamycin), is very effective in CNV suppression.
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