The SDF-1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization

Raquel Formica, Jikui Shen, Sean F. Hackett, Shu Kachi, Hideo Akiyama, Katsuji Kiuchi, Katsutoshi Yokoi, Maria C. Hatara, Thomas Lauer, Sadia Aslam, Yuan Yuan Gong, Wei Hong Xiao, Naw Htee Khu, Catherine Thut, Peter A Campochiaro

Research output: Contribution to journalArticle

Abstract

Hypoxia causes increased expression of several proteins that have the potential to promote neovascularization. Vascular endothelial growth factor (VEGF) is up-regulated by hypoxia in the retina and plays a central role in the development of several types of ocular neovascularization, but the effects of other hypoxia-regulated proteins are less clear. Stromal-derived factor-1 (SDF-1) and its receptor, CXCR4, have hypoxia response elements in the promoter regions of their genes and are increased in hypoxic liver and heart. In this study, we found that SDF-1 and CXCR4 are increased in hypoxic retina, with SDF-1 localized in glial cells primarily near the surface of the retina and CXCR4 localized in bone marrow-derived cells. Glial cells also expressed CXCR4, which suggested the possibility of autocrine stimulation, but influx of bone marrow-derived cells is the major source of increased levels of CXCR4. High levels of VEGF in the retina in the absence of hypoxia also increased levels of Cxcr4 and Sdf1 mRNA. CXCR4 antagonists reduced influx of bone marrow-derived cells into ischemic retina and strongly suppressed retinal neovascularization, VEGF-induced subretinal neovascularization, and choroidal neovascularization. These data suggest that SDF-1 and CXCR4 contribute to the involvement of bone marrowderived cells and collaborate with VEGF in the development of several types of ocular neovascularization. They provide new targets for therapeutic intervention that may help to bolster and supplement effects obtained with VEGF antagonists.

Original languageEnglish (US)
Pages (from-to)3219-3230
Number of pages12
JournalFASEB Journal
Volume21
Issue number12
DOIs
StatePublished - Oct 2007

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CXCR4 Receptors
angiogenesis
vascular endothelial growth factors
Vascular Endothelial Growth Factor A
Retina
retina
eyes
hypoxia
Ligands
Bone
receptors
Bone Marrow Cells
bone marrow
Neuroglia
neuroglia
antagonists
Retinal Neovascularization
Choroidal Neovascularization
cells
Response Elements

Keywords

  • Age-related macular degeneration
  • Angiogenesis
  • Chemokines
  • Diabetic retinopathy
  • Inflammation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology
  • Medicine(all)

Cite this

The SDF-1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization. / Formica, Raquel; Shen, Jikui; Hackett, Sean F.; Kachi, Shu; Akiyama, Hideo; Kiuchi, Katsuji; Yokoi, Katsutoshi; Hatara, Maria C.; Lauer, Thomas; Aslam, Sadia; Gong, Yuan Yuan; Xiao, Wei Hong; Khu, Naw Htee; Thut, Catherine; Campochiaro, Peter A.

In: FASEB Journal, Vol. 21, No. 12, 10.2007, p. 3219-3230.

Research output: Contribution to journalArticle

Formica, R, Shen, J, Hackett, SF, Kachi, S, Akiyama, H, Kiuchi, K, Yokoi, K, Hatara, MC, Lauer, T, Aslam, S, Gong, YY, Xiao, WH, Khu, NH, Thut, C & Campochiaro, PA 2007, 'The SDF-1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization', FASEB Journal, vol. 21, no. 12, pp. 3219-3230. https://doi.org/10.1096/fj.06-7359com
Formica, Raquel ; Shen, Jikui ; Hackett, Sean F. ; Kachi, Shu ; Akiyama, Hideo ; Kiuchi, Katsuji ; Yokoi, Katsutoshi ; Hatara, Maria C. ; Lauer, Thomas ; Aslam, Sadia ; Gong, Yuan Yuan ; Xiao, Wei Hong ; Khu, Naw Htee ; Thut, Catherine ; Campochiaro, Peter A. / The SDF-1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization. In: FASEB Journal. 2007 ; Vol. 21, No. 12. pp. 3219-3230.
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abstract = "Hypoxia causes increased expression of several proteins that have the potential to promote neovascularization. Vascular endothelial growth factor (VEGF) is up-regulated by hypoxia in the retina and plays a central role in the development of several types of ocular neovascularization, but the effects of other hypoxia-regulated proteins are less clear. Stromal-derived factor-1 (SDF-1) and its receptor, CXCR4, have hypoxia response elements in the promoter regions of their genes and are increased in hypoxic liver and heart. In this study, we found that SDF-1 and CXCR4 are increased in hypoxic retina, with SDF-1 localized in glial cells primarily near the surface of the retina and CXCR4 localized in bone marrow-derived cells. Glial cells also expressed CXCR4, which suggested the possibility of autocrine stimulation, but influx of bone marrow-derived cells is the major source of increased levels of CXCR4. High levels of VEGF in the retina in the absence of hypoxia also increased levels of Cxcr4 and Sdf1 mRNA. CXCR4 antagonists reduced influx of bone marrow-derived cells into ischemic retina and strongly suppressed retinal neovascularization, VEGF-induced subretinal neovascularization, and choroidal neovascularization. These data suggest that SDF-1 and CXCR4 contribute to the involvement of bone marrowderived cells and collaborate with VEGF in the development of several types of ocular neovascularization. They provide new targets for therapeutic intervention that may help to bolster and supplement effects obtained with VEGF antagonists.",
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AU - Formica, Raquel

AU - Shen, Jikui

AU - Hackett, Sean F.

AU - Kachi, Shu

AU - Akiyama, Hideo

AU - Kiuchi, Katsuji

AU - Yokoi, Katsutoshi

AU - Hatara, Maria C.

AU - Lauer, Thomas

AU - Aslam, Sadia

AU - Gong, Yuan Yuan

AU - Xiao, Wei Hong

AU - Khu, Naw Htee

AU - Thut, Catherine

AU - Campochiaro, Peter A

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N2 - Hypoxia causes increased expression of several proteins that have the potential to promote neovascularization. Vascular endothelial growth factor (VEGF) is up-regulated by hypoxia in the retina and plays a central role in the development of several types of ocular neovascularization, but the effects of other hypoxia-regulated proteins are less clear. Stromal-derived factor-1 (SDF-1) and its receptor, CXCR4, have hypoxia response elements in the promoter regions of their genes and are increased in hypoxic liver and heart. In this study, we found that SDF-1 and CXCR4 are increased in hypoxic retina, with SDF-1 localized in glial cells primarily near the surface of the retina and CXCR4 localized in bone marrow-derived cells. Glial cells also expressed CXCR4, which suggested the possibility of autocrine stimulation, but influx of bone marrow-derived cells is the major source of increased levels of CXCR4. High levels of VEGF in the retina in the absence of hypoxia also increased levels of Cxcr4 and Sdf1 mRNA. CXCR4 antagonists reduced influx of bone marrow-derived cells into ischemic retina and strongly suppressed retinal neovascularization, VEGF-induced subretinal neovascularization, and choroidal neovascularization. These data suggest that SDF-1 and CXCR4 contribute to the involvement of bone marrowderived cells and collaborate with VEGF in the development of several types of ocular neovascularization. They provide new targets for therapeutic intervention that may help to bolster and supplement effects obtained with VEGF antagonists.

AB - Hypoxia causes increased expression of several proteins that have the potential to promote neovascularization. Vascular endothelial growth factor (VEGF) is up-regulated by hypoxia in the retina and plays a central role in the development of several types of ocular neovascularization, but the effects of other hypoxia-regulated proteins are less clear. Stromal-derived factor-1 (SDF-1) and its receptor, CXCR4, have hypoxia response elements in the promoter regions of their genes and are increased in hypoxic liver and heart. In this study, we found that SDF-1 and CXCR4 are increased in hypoxic retina, with SDF-1 localized in glial cells primarily near the surface of the retina and CXCR4 localized in bone marrow-derived cells. Glial cells also expressed CXCR4, which suggested the possibility of autocrine stimulation, but influx of bone marrow-derived cells is the major source of increased levels of CXCR4. High levels of VEGF in the retina in the absence of hypoxia also increased levels of Cxcr4 and Sdf1 mRNA. CXCR4 antagonists reduced influx of bone marrow-derived cells into ischemic retina and strongly suppressed retinal neovascularization, VEGF-induced subretinal neovascularization, and choroidal neovascularization. These data suggest that SDF-1 and CXCR4 contribute to the involvement of bone marrowderived cells and collaborate with VEGF in the development of several types of ocular neovascularization. They provide new targets for therapeutic intervention that may help to bolster and supplement effects obtained with VEGF antagonists.

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