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 Anthony Lutty, Maria B. Grant

Research output: Contribution to journalArticle

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

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Choroidal Neovascularization
Vascular Endothelial Growth Factor A
Intercellular Signaling Peptides and Proteins
Lasers
Angiogenesis Modulating Agents
Bruch Membrane
Messenger RNA
Blocking Antibodies
Choroid
Retinal Pigment Epithelium
Neutralizing Antibodies
Ganglia
Thymidine
Real-Time Polymerase Chain Reaction
Rupture
Endothelial Cells
Lung
Wounds and Injuries

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Sengupta, N., Afzal, A., Caballero, S., Chang, K. H., Shaw, L. C., Pang, J. J., ... Grant, M. B. (2010). Paracrine modulation of CXCR4 by IGF-1 and VEGF: Implications for choroidal neovascularization. Investigative Ophthalmology and Visual Science, 51(5), 2697-2704. https://doi.org/10.1167/iovs.09-4137

Paracrine modulation of CXCR4 by IGF-1 and VEGF : Implications for choroidal neovascularization. / Sengupta, Nilanjana; Afzal, Aqeela; Caballero, Sergio; Chang, Kyung Hee; Shaw, Lynn C.; Pang, Ji Jing; Bond, Vincent C.; Bhutto, Imran; Baba, Takayuki; Lutty, Gerard Anthony; Grant, Maria B.

In: Investigative Ophthalmology and Visual Science, Vol. 51, No. 5, 05.2010, p. 2697-2704.

Research output: Contribution to journalArticle

Sengupta, N, Afzal, A, Caballero, S, Chang, KH, Shaw, LC, Pang, JJ, Bond, VC, Bhutto, I, Baba, T, Lutty, GA & Grant, MB 2010, 'Paracrine modulation of CXCR4 by IGF-1 and VEGF: Implications for choroidal neovascularization', Investigative Ophthalmology and Visual Science, vol. 51, no. 5, pp. 2697-2704. https://doi.org/10.1167/iovs.09-4137
Sengupta, Nilanjana ; Afzal, Aqeela ; Caballero, Sergio ; Chang, Kyung Hee ; Shaw, Lynn C. ; Pang, Ji Jing ; Bond, Vincent C. ; Bhutto, Imran ; Baba, Takayuki ; Lutty, Gerard Anthony ; Grant, Maria B. / Paracrine modulation of CXCR4 by IGF-1 and VEGF : Implications for choroidal neovascularization. In: Investigative Ophthalmology and Visual Science. 2010 ; Vol. 51, No. 5. pp. 2697-2704.
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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.",
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T1 - Paracrine modulation of CXCR4 by IGF-1 and VEGF

T2 - Implications for choroidal neovascularization

AU - Sengupta, Nilanjana

AU - Afzal, Aqeela

AU - Caballero, Sergio

AU - Chang, Kyung Hee

AU - Shaw, Lynn C.

AU - Pang, Ji Jing

AU - Bond, Vincent C.

AU - Bhutto, Imran

AU - Baba, Takayuki

AU - Lutty, Gerard Anthony

AU - Grant, Maria B.

PY - 2010/5

Y1 - 2010/5

N2 - 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.

AB - 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.

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