Advertisement

γ-Secretase Regulates VEGFR-1 Signalling in Vascular Endothelium and RPE

  • Michael E. Boulton
  • Jun Cai
  • Maria B. Grant
  • Yadan Zhang
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 613)

Neovascular diseases of the eye include retinopathy of prematurity (ROP), proliferative diabetic retinopathy (PDR), and the exudative or “wet” form of age-relatedmacular degeneration (AMD). Together these diseases affect all age groups and are the leading causes of vision impairment in developed nations (Lee et al., 1998). The collective evidence suggests that the vascular endothelial growth factor (VEGF) family is critical for ocular angiogensis (Cai and Boulton, 2002; Grant et al., 2004). First, increasing VEGF in animal models promotes ocular neovascularization and this can be reversed by neutralizing VEGF or its receptors(vanWijngaarden et al., 2005; Witmer et al., 2003). Second, VEGF is hypoxia-inducible and thus dramatically upregulated by the hypoxic environment in ROP and PDR (Grant et al., 2004; Witmer et al., 2003). Third, treatment of AMD patients with CNV with VEGF inhibitors such as Macugen or Lucentis significantly reduces choroidal neovascularization (vanWijngaarden et al., 2005).

Keywords

Vascular Endothelial Growth Factor Vascular Endothelial Growth Factor Receptor Proliferative Diabetic Retinopathy Vascular Endothelial Growth Factor Inhibitor Intramembrane Proteolysis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Autiero, M., et al., 2003. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med. 9, 936–43.PubMedCrossRefGoogle Scholar
  2. Bussolati, B., et al., 2001. Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide. Am J Pathol. 159, 993–1008.PubMedGoogle Scholar
  3. Cai, J., Boulton, M., 2002. The pathogenesis of diabetic retinopathy: old concepts and new questions. Eye. 16, 242–60.PubMedCrossRefGoogle Scholar
  4. Cai, J., et al., 2006. Pigment epithelium-derived factor inhibits angiogenesis via regulated intracellular proteolysis of vascular endothelial growth factor receptor 1. J Biol Chem. 281, 3604–13.PubMedCrossRefGoogle Scholar
  5. Ferrara, N., 2005. The role of VEGF in the regulation of physiological and pathological angiogenesis. Exs. 209–31.Google Scholar
  6. Grant, M. B., et al., 2004. The role of growth factors in the pathogenesis of diabetic retinopathy. Expert Opin Investig Drugs. 13, 1275–93.PubMedCrossRefGoogle Scholar
  7. Hellstrom, M., et al., 2007. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature. 445, 776–80.PubMedCrossRefGoogle Scholar
  8. Hiratsuka, S., et al., 1998. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci U S A. 95, 9349–54.PubMedCrossRefGoogle Scholar
  9. Kanning, K. C., et al., 2003. Proteolytic processing of the p75 neurotrophin receptor and two homologs generates C-terminal fragments with signaling capability. J Neurosci. 23, 5425–36.PubMedGoogle Scholar
  10. Landman, N., Kim, T. W., 2004. Got RIP? Presenilin-dependent intramembrane proteolysis in growth factor receptor signaling. Cytokine Growth Factor Rev. 15, 337–51.PubMedCrossRefGoogle Scholar
  11. Lee, P., et al., 1998. Ocular neovascularization: an epidemiologic review. Surv Ophthalmol. 43, 245–69.PubMedCrossRefGoogle Scholar
  12. Luttun, A., et al., 2002. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med. 8, 831–40.PubMedGoogle Scholar
  13. Marambaud, P., et al., 2002. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. Embo J. 21, 1948–56.PubMedCrossRefGoogle Scholar
  14. Mastrangelo, P., et al., 2005. Dissociated phenotypes in presenilin transgenic mice define functionally distinct gamma-secretases. Proc Natl Acad Sci U S A. 102, 8972–7.PubMedCrossRefGoogle Scholar
  15. Murakami, Y., et al., 2006. Ets-1-dependent Expression of vascular endothelial growth factor receptors is activated by latency-associated nuclear antigen of Kaposi’s Sarcoma-associated herpesvirus through interaction with daxx. J Biol Chem. 281, 28113–21.PubMedCrossRefGoogle Scholar
  16. Nakajima, M., et al., 2006. Presenilin-1 controls the growth and differentiation of endothelial progenitor cells through its beta-catenin-binding region. Cell Biol Int. 30, 239–43.PubMedCrossRefGoogle Scholar
  17. Nakajima, M., et al., 2003. Abnormal blood vessel development in mice lacking presenilin-1. Mech Dev. 120, 657–67.PubMedCrossRefGoogle Scholar
  18. Ni, C. Y., et al., 2001. gamma-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science. 294, 2179–81.PubMedCrossRefGoogle Scholar
  19. Nozaki, M., et al., 2006. Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A. J Clin Invest. 116, 422–9.PubMedCrossRefGoogle Scholar
  20. Rahimi, N., 2006. VEGFR-1 and VEGFR-2: two non-identical twins with a unique physiognomy. Front. Biosci. 11, 818–829.Google Scholar
  21. Rahimi, N., et al., 2000. Receptor chimeras indicate that the vascular endothelial growth factor receptor-1 (VEGFR-1) modulates mitogenic activity of VEGFR-2 in endothelial cells. J Biol Chem. 275, 16986-92.PubMedCrossRefGoogle Scholar
  22. Rawson, R. B., 2002. Regulated intramembrane proteolysis: from the endoplasmic reticulum to the nucleus. Essays Biochem. 38, 155–68.PubMedGoogle Scholar
  23. Roberts, D. M., et al., 2004. The vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR-1) modulates Flk-1 (VEGFR-2) signaling during blood vessel formation. Am J Pathol. 164, 1531–5.PubMedGoogle Scholar
  24. Sainson, R. C., et al., 2005. Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis. Faseb J. 19, 1027–29.PubMedGoogle Scholar
  25. Selkoe, D., Kopan, R., 2003. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci. 26, 565–97.PubMedCrossRefGoogle Scholar
  26. Shen, J., et al., 2006. Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1. Gene Ther. 13, 225–34.PubMedCrossRefGoogle Scholar
  27. Shibuya, M., Claesson-Welsh, L., 2006. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res. 312, 549–60.PubMedCrossRefGoogle Scholar
  28. vanWijngaarden, P., et al., 2005. Inhibitors of ocular neovascularization: promises and potential problems. Jama. 293, 1509–13.PubMedCrossRefGoogle Scholar
  29. Witmer, A. N., et al., 2003. Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res. 22, 1–29.PubMedCrossRefGoogle Scholar
  30. Wolfe, M. S., 2006. The gamma-secretase complex: membrane-embedded proteolytic ensemble. Biochemistry. 45, 7931–39.PubMedCrossRefGoogle Scholar
  31. Zeng, H., et al., 2001. Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) peceptor-1 down-modulates VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent pathways. J Biol Chem. 276, 26969–79.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Michael E. Boulton
    • 1
  • Jun Cai
    • 1
  • Maria B. Grant
    • 2
  • Yadan Zhang
    • 3
  1. 1.Ophthalmology and Visual SciencesUniversity of Texas Medical BranchGalveston
  2. 2.Pharmacology and TherapeuticsUniversity of FloridaGainesville
  3. 3.Optometry and Vision SciencesCardiff UniversityWalesUK

Personalised recommendations