title: Junctional adhesion molecule-A regulates vascular endothelial growth factor receptor-2 signaling-dependent mouse corneal wound healing.
abstract: Inflammation and angiogenesis are integral parts of wound healing. However, excessive and persistent wound-induced inflammation and angiogenesis in an avascular tissue such as the cornea may be associated with scarring and visual impairment. Junctional adhesion molecule A (Jam-A) is a tight junction protein that regulates leukocyte transmigration as well as fibroblast growth factor-2 (FGF-2)-induced angiogenesis. However its function in wound-induced inflammation and angiogenesis is still unknown. In this study, we report spontaneous corneal opacity in Jam-A deficient mice associated with inflammation, angiogenesis and the presence of myofibroblasts. Since wounds and/or corneal infections cause corneal opacities, we tested the role of Jam-A in wound-induced inflammation, angiogenesis and scarring by subjecting Jam-A deficient mice to full thickness corneal wounding. Analysis of these wounds demonstrated increased inflammation, angiogenesis, and increased number of myofibroblasts thereby indicating that Jam-A regulates the wound-healing response by controlling wound-induced inflammation, angiogenesis and scarring in the cornea. These effects were not due to inflammation alone since the inflammation-induced wound-healing response in Jam-A deficient mice was similar to wild type mice. In order to determine the molecular mechanism associated with the observed aberrant corneal wound healing in Jam-A deficient mice, we assessed the expression of the components of vascular endothelial growth factor A (VEGF-A)/vascular endothelial growth factor receptor- 2(VEGFR-2) signaling pathway. Interestingly, we observed increased levels of VEGF-A mRNA in Jam-A deficient eyes. We also observed nuclear localization of phosphorylated SMAD3 (pSMAD3) indicative of TGFβ pathway activation in the Jam-A deficient eyes. Furthermore the increased wound-induced corneal inflammation, angiogenesis, and scarring in Jam-A deficient mice was attenuated by treatment with DC101, an anti-vascular endothelial growth factor receptor-2 (VEGFR-2) antibody. Our results suggest that in the absence of Jam-A, the VEGF-A/VEGFR-2 pathway is upregulated, thereby augmenting wound induced corneal inflammation, angiogenesis, and myofibroblast accumulation leading to scarring.
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, Delaware, United States of America.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Melinda K
authors.initials: MK
authors.lastname: Duncan
authors.forename: Ulhas P
authors.initials: UP
authors.lastname: Naik
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D065306:Corneal Injuries; D003318:Corneal Opacity / Q000209:etiology / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000503:physiopathology*; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D017931:DNA Primers; C498686:F11r protein, mouse; D011956:Receptors, Cell Surface; D040301:Vascular Endothelial Growth Factor Receptor-2