Choroidal neovascularisation (CNV) is the main complication of age-related macular degeneration, the leading cause of blindness in the elderly. The steps to development of CNV involve endothelial cell adhesion, migration, proliferation and extracellular matrix production. The newly formed vessels from the choroids portion of the posterior eye then penetrate Bruch’s membrane (a subretinal layer) and lead to edema, retinal detachment and permanent loss of vision.
Important mediators of this process are receptor tyrosine kinases. These include the well known VEGF receptors as well as the Tie receptor for angiopoietins and the Eph receptors for Ephrin binding. Eph B4 and its cognate ligand Ephrin B2 profoundly influence angiogenesis. Ephrin B2 is expressed in the arterial angioblast and the endothelial and perivascular mesenchymal cells, whereas Eph B4 is predominantly expressed in the venous lineage. During development, these establish a hierarchical pattern of the vasculature. Their role in the adult vasculature is unknown.
In conjunction with Vasgene Therapeutics, He et al., have studied the effect of a soluble version of EphB4 on CNV in vitro and in vivo. As might be expected, the soluble EphB4 (sEphB4) acts as a dominant negative; competing for available Ephrin B2. The authors show a clear antagonism of VEGF induced migration in choroidal endothelial cells in the Boyden chamber assay. Using a collagen matrix, the authors go on to show that VEGF induced tube formation, the precursor to capillary formation, is efficiently down regulated by sEphB4.
Finally, and most persuasively, the authors show a clear reduction in CNV produced in an experimental model using laser coagulation in rats. After laser treatment, the rats were administered sEphB4 by intravitreal injection. Fluorescein leakage, a sign of immature CNV vessels, was reduced. The size of lesion introduced by Laser was also reduced as a function of time post treatment, and the number of CD31-positive cells (an endothelial marker) was greatly reduced by sEphB4 introduction.
These exciting results highlight a new target for antiangiogenic therapy. The use of soluble receptor tyrosine kinases forms a novel therapeutic approach that might also be used to target multiple signaling pathways (such as roundabout, plexin, neuropilin, and ‘unc’ receptors) simultaneously and lead to cures for diseases such as cancer and retinal dystrophies that depend on angiogenesis for their pathology.
Message posted by: Simon Chandler