Paracrine modulation of CXCR4 by IGF-1 and VEGF: Implications for choroidal neovascularization

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

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2697-2704
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume51
Issue number5
DOIs
StatePublished - May 2010

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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