VEGF via VEGF receptor-1 (Flt-1) mimics preeclamptic plasma in inhibiting uterine blood vessel relaxation in pregnancy: Implications in the pathogenesis of preeclampsia

Preeclampsia is a multisystem disorder characterized by hypertension and pr oteinuria. There is accumulating evidence that this is a disease of the end othelium, with an as-yet unidentified circulating factor, or factors, causi ng the observed alteration in vascular function. We previously reported tha t the function of myometrial vessels is altered on exposure to plasma from women with preeclampsia. Vascular endothelial growth factor (VEGF) is an an giogenic growth factor that acts via two high-affinity receptors (KDR and F lt-1), and its production is increased in preeclampsia. Here we report that VEGf and its Flt-1 receptor may play a pivotal role in the altered vascula r function of preeclampsia. Myometrial resistance vessels were obtained at the time of cesarean section. Using the Mulvany wire myograph, the endothel ium-dependent behavior of these vessels was studied. Incubation of vessels from pregnant women with VEGf resulted in a reduction of endothelium-depend ent relaxation that mimicked the reduction induced by plasma from women wit h preeclampsia. The altered function that occurred upon exposure of vessels to VEGF or plasma from women with preeclampsia did not occur when plasma w as incubated with antibodies to VEGf before vessel incubation. The presence of an anti-KDR receptor antibody had no effect on VEGF response. However, in the presence of an anti-Flt-1 receptor antibody, VEGF or plasma from wom en with preeclampsia no longer attenuated the endothelium-dependent relaxat ion (p < 0.05). The changes observed with VEGF and plasma from women with p reeclampsia and their subsequent blockade with anti-VEGF antibody and anti- Flt-1 receptor antibody strongly suggest that VEGF acting through the Flt-1 receptor is pivotal in the pathogenesis of this disease.