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Nilanjana Sengupta, Aqeela Afzal, Sergio Caballero, Kyung-Hee Chang, Lynn C. Shaw, Ji-Jing Pang, Vincent C. Bond, Imran Bhutto, Takayuki Baba, Gerard A. Lutty, Maria B. Grant; Paracrine Modulation of CXCR4 by IGF-1 and VEGF: Implications for Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2010;51(5):2697-2704. doi: 10.1167/iovs.09-4137.
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Modulators of angiogenesis typically work in an orchestrated manner. The authors examined the interaction between insulinlike growth factor (IGF)-1, vascular endothelial growth factor (VEGF), and stromal derived factor (SDF)-1 in vivo and in vitro using angiogenesis models.
The angiogenic effect of SDF-1, alone or in combination with IGF-1 and VEGF, was assessed in human lung microvascular endothelial cells using capillary tube formation and thymidine incorporation. Immunohistochemical analysis for CD31, SDF-1, and CXCR4 was performed on mouse eyes 2 weeks after the initiation of laser rupture of Bruch's membrane, a choroidal neovascularization (CNV) model. CXCR4 antagonist and CXCR4 blocking antibody were tested on inhibition of CNV lesion size in this model. Real-time PCR was used to determine mRNA levels for SDF-1, VEGF, IGF-1, and their cognate receptors in the retinal pigment epithelium/choroid complex of mice that underwent this CNV model.
IGF-1 and VEGF demonstrated an additive effect on SDF-1–induced in vitro angiogenesis. CXCR4 immunoreactivity was present in both normal and laser-injured mice at the laser burn site and at the ganglion cell layer, the anterior portion of the inner nuclear layer, photoreceptors, and choroidal stroma. SDF-1 was observed in identical locations but was not seen in photoreceptors. mRNA levels for SDF-1, VEGF, and IGF-1 and their receptors were increased after laser injury. CXCR4-neutralizing antibody reduced neovascularization when injected subretinally but not intraperitoneally or intravitreally.
The potent proangiogenic factors IGF-1 and VEGF both stimulate SDF-1–induced angiogenesis. Local inhibition of CXCR4 is required for an antiangiogenic effect in CNV lesions.
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