WonKyung Cho1, Sharad K Mittal1, Elsayed Elbasiony1, Sunil K Chauhan2. 1. Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA, USA. 2. Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA, USA. Electronic address: sunil_chauhan@meei.harvard.edu.
Abstract
PURPOSE: Mast cells, historically known for their effector function in the induction of allergic diseases, reside in all vascularized tissues of the body in particular proximity to blood and lymphatic vessels. As neighboring sentinel cells to blood vessels, mast cells have been associated with angiogenesis. Here we assess the direct contribution of mast cells to neovascularization at the ocular surface. METHODS: Corneal neovascularization was induced by placing a single figure-of-eight intrastromal suture 1 mm from the limbus in mast cell-deficient (cKitW-sh), C57BL/6, and Balb/c mice. Corneas were harvested at 6 h post-suture to quantify cKit+FcεR1+ mast cells using flow cytometry and tear wash was collected within 6 h to measure β-hexosaminidase and tryptase. Neovascularization was assessed using slit-lamp biomicroscope and immunohistochemistry analysis of corneas harvested on day 4 post-suture. To investigate the effects of mast cells on blood vessel growth, mast cells were co-cultured with vascular endothelial cells (VECs), and tube formation and proliferation of VECs were measured. 2% cromolyn was administered locally to inhibit mast cell activation in vivo. RESULTS: Placement of corneal suture activates ocular surface mast cells, which infiltrate into the cornea adjacent to new vessels. Mast cell-deficient mice develop significantly fewer new vessels following suture placement. Mast cells directly promote VEC proliferation and tube formation, partly through secreting high levels of VEGF-A. Pharmacological inhibition of mast cell activation results in significantly less corneal neovascularization. CONCLUSION: Our data demonstrate that ocular surface mast cells are critical to corneal neovascularization, suggesting mast cells as a potential therapeutic target in the treatment of corneal neovascularization.
PURPOSE: Mast cells, historically known for their effector function in the induction of allergic diseases, reside in all vascularized tissues of the body in particular proximity to blood and lymphatic vessels. As neighboring sentinel cells to blood vessels, mast cells have been associated with angiogenesis. Here we assess the direct contribution of mast cells to neovascularization at the ocular surface. METHODS:Corneal neovascularization was induced by placing a single figure-of-eight intrastromal suture 1 mm from the limbus in mast cell-deficient (cKitW-sh), C57BL/6, and Balb/c mice. Corneas were harvested at 6 h post-suture to quantify cKit+FcεR1+ mast cells using flow cytometry and tear wash was collected within 6 h to measure β-hexosaminidase and tryptase. Neovascularization was assessed using slit-lamp biomicroscope and immunohistochemistry analysis of corneas harvested on day 4 post-suture. To investigate the effects of mast cells on blood vessel growth, mast cells were co-cultured with vascular endothelial cells (VECs), and tube formation and proliferation of VECs were measured. 2% cromolyn was administered locally to inhibit mast cell activation in vivo. RESULTS: Placement of corneal suture activates ocular surface mast cells, which infiltrate into the cornea adjacent to new vessels. Mast cell-deficient mice develop significantly fewer new vessels following suture placement. Mast cells directly promote VEC proliferation and tube formation, partly through secreting high levels of VEGF-A. Pharmacological inhibition of mast cell activation results in significantly less corneal neovascularization. CONCLUSION: Our data demonstrate that ocular surface mast cells are critical to corneal neovascularization, suggesting mast cells as a potential therapeutic target in the treatment of corneal neovascularization.
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