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A. Markowska, F.-T. Liu, N. Panjwani; Galectin-3 Influences VEGF- and bFGF-Mediated Angiogenesis by Modulating the Activity of vβ3 Integrin. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2036. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Angiogenesis is a key factor in the pathogenesis of a number of ocular diseases including corneal graft failure, age-related macular degeneration and diabetic retinopathy. In this study, we investigate the mechanism of a carbohydrate-binding protein, galectin-3, in VEGF- and bFGF-mediated angiogenesis
Capillary tubule formation assays and cell migration assays were performed using HUVECs in which expression of galectin-3 and GnTV were knocked-down to evaluate the significance of galectin-3 in VEGF- and bFGF-mediated angiogenesis in vitro. Experiments were also performed in the presence of integrin blocking antibodies, saccharide inhibitors of galectins and dominant negative galectin-3. Mouse corneal micropocket assays were performed in GnTV-/-, GnTV+/+, Gal3-/- and Gal3+/+ to evaluate angiogenesis in vivo.
Saccharide inhibitors of galectin-3 as well as dominant negative galectin-3 significantly reduced VEGF- and bFGF-mediated angiogenesis in vitro. VEGF- and bFGF-mediated angiogenic response was also reduced in galectin-3 knockdown HUVECs and in Gal3-/- animals as compared to the wild type mice. Integrin αvβ3, a critical component of the VEGF and bFGF angiogenic cascade, was identified as the major galectin-3-binding protein in human umbilical vein endothelial cells (HUVECs) and anti-αv, -β3 as well as -αvβ3 integrin function-blocking antibodies significantly inhibited the galectin-3-induced angiogenesis. Furthermore, galectin-3 promoted clustering of integrin αvβ3 and activated focal adhesion kinase (FAK). Disruption of GnTV, an enzyme which synthesizes high affinity glycan ligands for galectin-3, diminished VEGF- and bFGF-mediated angiogenesis in vitro. Furthermore, VEGF- and bFGF-mediated angiogenesis was reduced in GnTV-/- animals as compared to the wild type mice.
Galectin-3 influences VEGF- and bFGF-mediated angiogenic response by modulating the function of integrin αvβ3 and as such may serve as a valuable target for effective angiogenesis inhibition in a number of devastating clinical conditions including corneal graft failure, age- related macular degeneration and diabetic retinopathy.
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