Abstract
Purpose :
Pathological retinal neovascularization is a clinical manifestation of various proliferative retinopathies, including retinopathy of prematurity (ROP), diabetic retinopathy, and the wet form of macular degeneration. A characteristic feature of these conditions is the presence of hypoxic areas and over-expression of the proangiogenic vascular endothelial growth factor (VEGF). Treatments of these neovascular diseases using a laser or anti-VEGF therapies not only induce various local and systemic side effects but also are only partially effective.
Methods :
Using a murine model of oxygen-induced retinopathy (OIR) and human retinal microvascular endothelial cells(HRMVECs), we are trying to understand the significance of IL-33/ST2L-signaling on retinal endothelial sprouting, migration, and tube formation leading to retinal neovascularization.
Results :
Here, using a murine model of oxygen-induced retinopathy, we found that either intravitreal injections of IL-33 siRNA or genetic deletion of IL-33 resulted in reduced neovascularization with no significant changes in the avascular area. These findings suggest a role for IL-33 in pathological neovascularization with little or no effect on the normal retinal repair. Interestingly, we observed that along with IL-33 activation, hypoxia also induces expression of ST2 transmembrane receptor (ST2L), both at mRNA and protein levels, with little or no effect on secretory ST2 (sST2) levels. Our in vitro experiments using human retinal microvascular endothelial cells as a model suggest the importance of IL-33/ST2L-signaling on endothelial cell migration, tube formation, and sprouting. Besides it, our in vitro and in vivo findings provide evidence that IL-33/ST2L-signaling via ADAMTS10 activation facilitates sprout formation and invasion of connective tissue through controlled degradation of extracellular matrix proteins (ECMs).
Conclusions :
These results strongly suggest that IL-33/ST2L-signaling plays a key role in retinal neovascularization and thus represents a new pharmacological target for the treatment of diseases where excessive neovascularization is the underlying pathology.
This is a 2020 ARVO Annual Meeting abstract.