Inhibitory Effects of SU5416, a Selective Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, on Experimental Corneal Neovascularization

Abstract

Purpose: Treatment of neovascularization in ocular diseases with vascular endothelial growth factor (VEGF) inhibition shows promising results. SU5416 is a low-molecular-weight tyrosine kinase inhibitor. It selectively inhibits the membrane-bound tyrosine kinase activity of VEGF-2 receptor (Flk-1/KDR) and blocks the intracellular signaling process. The aim of this study was to evaluate the effect of SU5416 on corneal neovascularization. Methods: Corneas were cauterized with silver nitrate/potassium nitrate sticks in 20 eyes of 20 BALB/C mice. In the study group (n = 10), SU5416 (25 mg/kg) dissolved in dimethyl sulfoxide was given as an intraperitoneal injection in a single daily dose for 7 days. The other group of 10 mice given intraperitoneal dimethyl sulfoxide alone served as a control group. After 7 days, corneal neovascularization was evaluated using photographs captured by fluorescein angiography. Colored photographs were taken by a biomicroscope with a digital camera. Data were expressed as mean neovascular length and mean number of new vessels for each animal. The values were computed and compared between the groups. Results: The mean burn stimulus intensities were not different between the groups. In the study group, the mean length of the vessels and the mean number of vessels were 0.49 ± 0.05 and 11.20 ± 1.69 mm, respectively. In the control group, the mean length of the vessels and the mean number of the vessels were 0.89 ± 0.11 and 17.80 ± 1.03 mm, respectively. There is a statistically significant difference in the mean length and the mean number of new vessels between the study and control groups (p < 0.001). Conclusion: Selective inhibition of VEGFR-2 (Flk-1/KDR) tyrosine kinase with SU5416 was shown to have an inhibitory effect on corneal neovascularization in this animal model. VEGFR-2 (Flk-1/KDR) tyrosine kinase inhibition may represent a different pathway for treatment of the neovascularization process in ocular pathologies. Fluorescein angiography photographs of new vessels on the cornea may provide a better evaluation of neovascularization than colored images in animal models.

NADPH oxidase 2 plays a role in experimental corneal neovascularization

“…Our findings align with previous studies that show that blocking the activity of Vegf-A with either Vegf-A receptor inhibitors or Vegf neutralizing antibodies suppresses neovascularization following corneal cautery [37,46,47]. In the present study we further demonstrated that Nox2 may play a role in Vegf mediated angiogenic responses following corneal cautery as we found reductions in neovascularization as well as gene and protein expression of Vegf-A and Flt1.…”

Endoglin interacts with VEGFR2 to promote angiogenesis

“…4 E ). Further, the VEGFR2 tyrosine kinase inhibitor, SU‐5416 (29–31) (Supplemental Fig. 4 D ), decreased the VEGF‐A‐mediated endoglin and VEGFR2 interaction (Fig.…”

Apatinib-loaded nanoparticles suppress vascular endothelial growth factor-induced angiogenesis and experimental corneal neovascularization

“…For example, treatment with SU5416, a selective inhibitor of VEGFR2 tyrosine kinase, had an inhibitory effect on alkali burn-induced corneal neovascularization in mice. 20 Regorafenib, an inhibitor of multiple tyrosine kinases including VEGFRs, inhibited corneal neovascularization in a similar animal model. 21 Treatment with oral small-molecule inhibitors of VEGFR reduced suture-induced hemangiogenesis in the cornea and enhanced the survival of allogenic corneal transplants in rats.…”