Inhibition of erythropoietin-producing hepatoma receptor B4 (EphB4) signalling suppresses the vascularisation and growth of endometriotic lesions

Abstract

Background and Purpose:The development of endometriotic lesions is cruciallydependent on the formation of new blood vessels. In the present study, we analysedwhether this process is regulated by erythropoietin-producing hepatoma receptor B4(EphB4) signalling.Experimental Approach:We first assessed the anti-angiogenic action of the EphB4inhibitor NVP-BHG712 in different in vitro angiogenesis assays. Then, endometrioticlesions were surgically induced in the dorsal skinfold chamber and peritonealcavity of NVP-BHG712- or vehicle-treated BALB/c mice. This allowed to study theeffect of EphB4 inhibition on their vascularisation and growth by means of intravitalfluorescence microscopy, high-resolution ultrasound imaging, histology andimmunohistochemistry.Key Results:Non-cytotoxic doses of NVP-BHG712 suppressed the migration, tubeformation and sprouting activity of both human dermal microvascular endothelialcells (HDMEC) and mouse aortic rings. Accordingly, we also detected a lower bloodvessel density in NVP-BHG712-treated endometriotic lesions. This was associatedwith a reduced lesion growth due to a significantly lower number of proliferatingstromal cells when compared to vehicle-treated controls.Conclusions and Implications:Inhibition of EphB4 signalling suppresses thevascularisation and growth of endometriotic lesions. Hence, EphB4 represents apromising pharmacological target for the treatment of endometriosis.