The role of leukocytes in ischemia‐driven neovascularisation

Abstract

Purpose Our research strategy has been to study VEGF‐A and the adaptive response to ischemia, with the aim of better understanding the benefit that VEGF‐A may bring to ischemic tissues, and to characterize the basis for the chaotic and poorly controlled neovascular response that usually accompanies ischemia in retinal diseases such as diabetic retinopathy. Methods Mice genetically engineered with deletion of the VEGF164 isoform were examined during normal vascular development of the retina and following oxygen‐induced retinopathy. Abnormal vascular growth and leukostasis were quantified. To study determinants of VEGF‐A involved in leukostasis, VEGF‐A mutants and VEGF‐A signaling antagonists were injected intraocularly Results Rather than focusing on the abolition of VEGF‐A signaling in ischemic retinal disease, we have tried to find ways to normalize the adaptive response. We previously demonstrated that inflammation was critical for the abnormal vascular response in OIR. Here we found that inflammation was driven by VEGF164, and that a cluster of residues in the heparin‐binding domain of VEGF164 were responsible for its heightened inflammatory activity compared to other VEGF‐A isoforms. This region of VEGF164 imparts high affinity binding to VEGFR1 Conclusion Data suggest that reducing VEGF‐VEGFR1 mediated inflammation, whilst preserving VEGF‐mediated angiogenesis, may be a strategy to help transform the unwanted pathological response to ischemia into a desirable outcome whereby new vessels sprout into the area of need and nurture the ischemic retina. Commercial interest