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The Corneal Micropocket Assay: A Model of Angiogenesis in the Mouse Eye
Published on: August 16, 2014
Paracrine modulation of CXCR4 by IGF-1 and VEGF: implications for choroidal neovascularization
Nilanjana Sengupta1, Aqeela Afzal, Sergio Caballero
1Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610-0267, USA.
Purpose:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF)-1 enhance stromal-derived factor (SDF)-1 induced angiogenesis. Local inhibition of CXCR4 is necessary to reduce choroidal neovascularization (CNV).
Area of Science:
- Ophthalmology
- Angiogenesis Research
- Molecular Biology
Background:
- Angiogenesis, the formation of new blood vessels, is a complex process involving multiple signaling pathways.
- Stromal-derived factor (SDF)-1, along with insulin-like growth factor (IGF)-1 and vascular endothelial growth factor (VEGF), are key players in regulating angiogenesis.
- Understanding the interplay between these factors is crucial for developing effective treatments for angiogenesis-related diseases, such as choroidal neovascularization (CNV).
Purpose of the Study:
- To investigate the interaction between SDF-1, IGF-1, and VEGF in angiogenesis.
- To examine the role of SDF-1 and its receptor CXCR4 in a mouse model of CNV.
- To assess the therapeutic potential of targeting CXCR4 for CNV treatment.
Main Methods:
- In vitro assessment of SDF-1, IGF-1, and VEGF effects on human lung microvascular endothelial cells using capillary tube formation and thymidine incorporation assays.
- Immunohistochemical analysis of CD31, SDF-1, and CXCR4 in a laser-induced CNV mouse model.
- Evaluation of CXCR4 antagonist and blocking antibody efficacy in reducing CNV lesion size.
- Real-time PCR to quantify mRNA levels of SDF-1, VEGF, IGF-1, and their receptors in the retinal pigment epithelium/choroid complex.
Main Results:
- IGF-1 and VEGF exhibited an additive proangiogenic effect on SDF-1-induced angiogenesis in vitro.
- CXCR4 and SDF-1 expression was detected at the laser injury site and in various retinal layers in mice.
- Laser injury increased the mRNA levels of SDF-1, VEGF, IGF-1, and their respective receptors.
- Subretinal injection of a CXCR4-neutralizing antibody significantly reduced neovascularization, while other administration routes were ineffective.
Conclusions:
- Potent proangiogenic factors IGF-1 and VEGF synergistically enhance SDF-1-mediated angiogenesis.
- Targeting the SDF-1/CXCR4 pathway holds promise for treating CNV.
- Local inhibition of CXCR4 is essential for achieving an antiangiogenic effect in CNV lesions.
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