VASCULAR ENDOTHELIAL GROWTH-FACTOR IS PRODUCED BY PERITONEAL-FLUID MACROPHAGES IN ENDOMETRIOSIS AND IS REGULATED BY OVARIAN-STEROIDS

Angiogenesis is important in the pathophysiology of endometriosis, a c ondition characterized by implantation of ectopic endometrium in the p eritoneal cavity. Vascular endothelial growth factor (VEGF) is a poten t angiogenic factor involved in physiological and pathological angioge nesis, and elevated levels of VEGF are found in peritoneal fluid of pa tients with endometriosis. Our aim was to investigate the site of expr ession and regulation of VEGF in endometriosis. VEGF immunoreactivity was found in tissue macrophages present in ectopic endometrium and in activated peritoneal fluid macrophages. Macrophage activation was high est in women with endometriosis, and media conditioned by peritoneal f luid macrophages from these women caused a VEGF-dependent increase in endothelial cell proliferation above that seen from normal women. Peri toneal fluid macrophages secreted VEGF in response to ovarian steroids , and this secretion was enhanced after activation with lipopolysaccha ride. Peritoneal fluid macrophages expressed receptors for steroid hor mones. VEGF receptors fit and KDR (kinase domain receptor) were also d etected, suggesting autocrine regulation. During the menstrual cycle, expression of fit was constant but that of KDR was increased in the lu teal phase, at which time the cells migrated in response to VEGF. KDR expression and the migratory response were significantly higher in pat ients with endometriosis. This study demonstrates that activated macro phages are a major source of VEGF in endometriosis and that this expre ssion is regulated directly by ovarian steroids.