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2009 OMIG, Abstract 21

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Blockade of Vascular Endothelial Growth Factor-C (VEGF-C) Suppresses Blood (Heme-) and Lymph-angiogenesis and Improves Corneal Transplant Survival.
A.R. Hajrasouliha, T. Funaki, Z. Sadrai, T. Hattori, R. Dana
Schepens Eye Research Institute, Harvard Medical School, Boston, MA.

Purpose: Survival of corneal transplants is compromised by presence of both blood and lymphatic vessels. Current therapies with anti-vascular endothelial growth factor-A (VEGF-A) antibodies (eg. Bevacizumab and Ranibizumab) target primarily blood vessel formation. In addition to hemangiogenesis, VEGF-C stimulates the growth of lymphatic vessels through its binding of the lymphatic endothelial receptor VEGFR-3. We thus hypothesized that VEGF-C blockade can concomitantly suppress lymphatic and blood vessel growth in the cornea, and thereby promotes graft survival
Methods: Corneal heme- and lymph-angiogenesis was induced by placement of three intrastromal sutures in corneas of BALB/c mice. Angiogenesis was quantified at two weeks after placement of sutures by double immunofluorescence staining of corneal flat mounts for blood vessels (CD31high, LYVE-1-) and lymphatic vessels (CD31 low, LYVE-1+).To block VEGF-C, intraperitoneal injections of anti-VEGF-C (VGX-100, Vegenics, Inc,.20 mg/kg) were started one day prior to surgery and continued on alternate days for 2 weeks. In the next set of experiments allogeneic C57BL/6 derived corneal buttons were placed on BALB/c mice and graft vascularization/opacification was followed up to 8 weeks in a masked fashion. The effect of VEGF-C blockade on corneal transplant survival was evaluated by intraperitoneal VGX-100 administration (as described above).
Results: Two weeks after corneal suture placement, blood vessels and lymphatic growth into the cornea were significantly reduced by anti-VEGF-C (53.4% reduction (p<0.01), 47.3% reduction (p<0.05), respectively). Moreover, anti-VEGF-C treatment doubled the corneal transplant survival at 8 weeks from 33% in the control group to 66 % (n = 20 in each group).
Conclusion: Blockade of VEGF-C effectively inhibits both hemangiogenesis and lymphangiogenesis in the cornea and doubles the rate of corneal allograft survival. These data suggest the potential role of VEGF-C among VEGF species in corneal transplant immunobiology.
Financial Support: NIH grant R01EY-12963 Dicsclosure Code: R

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