Extracellular Proteinases in Ocular Neovascularization

Summary

Principal Investigator: Arup Das
Abstract: Retinal neovascularization is the leading cause of blindness in the United States among working-age adults (diabetic retinopathy) and infants (retinopathy of prematurity). An important event of the angiogenesis cascade is the breakdown of the capillary basement membrane and the invasion and migration of microvascular endothelial cells through the extracellular matrix. This step of angiogenesis is partially dependent upon the expression and activity of proteinases, including urokinase (uPA) and its receptor. The activity of this enzyme is regulated by specific endogenous inhibitor, plasminogen activator inhibitor PAI-1. PAI-1 is elevated in the retina during new vessel formation and appears to be required for the neovascular response. The initiation of angiogenesis and the stimulation of proteinase and inhibitor expression are regulated by the activity of specific growth factors including the well known vascular endothelial growth factor (VEGF). Other factors may play important roles during this process including the hepatocyte growth factor (HGF) which has received little attention in terms of its function in ocular angiogenesis. Understanding the mechanisms of proteinase, proteinase inhibitor and growth factor expression, and identifying specific inhibitors of their functions may provide unique opportunities for the development of new therapeutic interventions for retinal neovascularization. This proposal will test the hypothesis that retinal neovascularization is facilitated by the expression of specific growth factors, extracelluar proteinases and their inhibitors, the inhibition of which may lead to new and useful therapies. The aims of this study which will address the hypothesis are: (1) To characterize the expression and role of PAI-1 in retinal neovascularization. We will use biochemical, histological and molecular techniques, including the use of knockout animals to address this aim. (2) To determine the expression and role of hepatocyte growth factor (HGF) in the regulation of proteinase expression and retinal capillary endothelial cell behavior in retinal neovascularization. Studies will focus on the role of HGF in regulating proteinase expression and endothelial cell behavior using wildtype and transgenic animals. (3) To determine if the extent of retinal neovascularization can be suppressed through the use of agents which directly or indirectly inhibit the function of PAI-1 or HGF. The results of these studies will allow us to further define the mechanisms involved in the formation of new vessels in the retina which can lead to serious visual complications, and whether a specific stage of the angiogenic process is an appropriate target for therapeutic intervention. Such an approach will provide a rational basis for the development of potentially powerful and effective therapeutics for ocular neovascularization.
Funding Period: ----------------1998 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Role of urokinase inhibitors in choroidal neovascularization
    Arup Das
    Division of Ophthalmology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
    Semin Ophthalmol 21:23-7. 2006
  2. ncbi Hepatocyte growth factor/scatter factor promotes retinal angiogenesis through increased urokinase expression
    Elizabeth S Colombo
    Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
    Invest Ophthalmol Vis Sci 48:1793-800. 2007
  3. ncbi Proteolytic degradation of VE-cadherin alters the blood-retinal barrier in diabetes
    Deepti Navaratna
    Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, USA
    Diabetes 56:2380-7. 2007
  4. pmc A peptide inhibitor of the urokinase/urokinase receptor system inhibits alteration of the blood-retinal barrier in diabetes
    Deepti Navaratna
    Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA
    FASEB J 22:3310-7. 2008
  5. pmc Suppression of retinal neovascularization with an antagonist to vascular endothelial cadherin
    Deepti Navaratna
    Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131 0001, USA
    Arch Ophthalmol 126:1082-8. 2008
  6. pmc Plasminogen activator inhibitor-1 (PAI-1) facilitates retinal angiogenesis in a model of oxygen-induced retinopathy
    Anupam Basu
    Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, USA
    Invest Ophthalmol Vis Sci 50:4974-81. 2009
  7. pmc A potential role for angiopoietin 2 in the regulation of the blood-retinal barrier in diabetic retinopathy
    Sampathkumar Rangasamy
    Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, USA
    Invest Ophthalmol Vis Sci 52:3784-91. 2011
  8. pmc Pericyte-derived sphingosine 1-phosphate induces the expression of adhesion proteins and modulates the retinal endothelial cell barrier
    Paul G McGuire
    Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
    Arterioscler Thromb Vasc Biol 31:e107-15. 2011

Scientific Experts

  • Paul G McGuire
  • Arup Das
  • Deepti Navaratna
  • Joann Maestas
  • Gina Menicucci
  • Sampathkumar Rangasamy
  • Ramprasad Srinivasan
  • Anupam Basu
  • Elizabeth S Colombo

Detail Information

Publications8

  1. ncbi Role of urokinase inhibitors in choroidal neovascularization
    Arup Das
    Division of Ophthalmology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
    Semin Ophthalmol 21:23-7. 2006
    ..As the current treatments of CNV are not optimal, the urokinase-uPAR system appears to be an attractive target for alternative pharamacological therapy for CNV...
  2. ncbi Hepatocyte growth factor/scatter factor promotes retinal angiogenesis through increased urokinase expression
    Elizabeth S Colombo
    Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
    Invest Ophthalmol Vis Sci 48:1793-800. 2007
    ....
  3. ncbi Proteolytic degradation of VE-cadherin alters the blood-retinal barrier in diabetes
    Deepti Navaratna
    Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, USA
    Diabetes 56:2380-7. 2007
    ....
  4. pmc A peptide inhibitor of the urokinase/urokinase receptor system inhibits alteration of the blood-retinal barrier in diabetes
    Deepti Navaratna
    Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA
    FASEB J 22:3310-7. 2008
    ..The ability of A6 to block retinal vascular permeability in diabetes suggests a potential therapeutic approach for the treatment of diabetic macular edema...
  5. pmc Suppression of retinal neovascularization with an antagonist to vascular endothelial cadherin
    Deepti Navaratna
    Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131 0001, USA
    Arch Ophthalmol 126:1082-8. 2008
    ..To examine the role of vascular endothelial cadherin (VE-cadherin) in cellular processes underlying angiogenesis and the effects of VE-cadherin inhibition on retinal angiogenesis...
  6. pmc Plasminogen activator inhibitor-1 (PAI-1) facilitates retinal angiogenesis in a model of oxygen-induced retinopathy
    Anupam Basu
    Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, USA
    Invest Ophthalmol Vis Sci 50:4974-81. 2009
    ..The aim of the present study was to investigate the role of the serine proteinase inhibitor plasminogen activator inhibitor -1 (PAI-1) in facilitating retinal angiogenesis...
  7. pmc A potential role for angiopoietin 2 in the regulation of the blood-retinal barrier in diabetic retinopathy
    Sampathkumar Rangasamy
    Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, USA
    Invest Ophthalmol Vis Sci 52:3784-91. 2011
    ..The expression of angiopoietins was analyzed in an animal model of diabetic retinopathy, and the role of Ang-2 in the regulation of diabetes-induced alterations of vascular permeability was characterized...
  8. pmc Pericyte-derived sphingosine 1-phosphate induces the expression of adhesion proteins and modulates the retinal endothelial cell barrier
    Paul G McGuire
    Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
    Arterioscler Thromb Vasc Biol 31:e107-15. 2011
    ..We determined the extent to which vascular pericytes could regulate pericyte-endothelial adhesion and the consequences that this disruption might have on the function of the endothelial barrier...