Inhibition of erythropoietin‐producing hepatoma receptor B4 (EphB4) signaling suppresses the vascularization and growth of endometriotic lesions

Background and Purpose: The development of endometriotic lesions is crucially dependent on the formation of new blood vessels. In the present study, we analyzed whether this process is regulated by erythropoietin-producing hepatoma receptor B4 (EphB4) signaling. Experimental Approach: We first assessed the anti-angiogenic action of the EphB4 inhibitor NVP-BHG712 in different in vitro angiogenesis assays. Moreover, we surgically induced en- dometriotic lesions in the dorsal skinfold chamber and peritoneal cavity of NVP-BHG712- or vehicle-treated BALB/c mice to study the effect of EphB4 inhibition on their vascularization and growth by means of intravital fluorescence microscopy, high-resolution ultrasound imag- ing, histology and immunohistochemistry. Key Results: Non-cytotoxic doses of NVP-BHG712 suppressed the migration, tube formation and sprouting activity of both human dermal microvascular endothelial cells (HDMEC) and mouse aortic rings. Accordingly, we also detected a lower blood vessel density in NVP- BHG712-treated endometriotic lesions. This was associated with a reduced lesion growth due to a significantly lower number of proliferating stromal cells when compared to vehicle-treated controls.