Recombinant Vascular Endothelial Growth Factor 121 Infusion Lowers Blood Pressure and Improves Renal Function in Rats With PlacentalIschemia-Induced Hypertension

Antagonism of vascular endothelial growth factor (VEGF) signaling by soluble fms-like tyrosine kinase 1 occurs during preeclampsia and is proposed to play an important role in the pathogenesis of preeclampsia. We reported recently that hypertension associated with chronic reductions in uteroplacental perfusion pressure (RUPP) is associated with increased soluble fms-like tyrosine kinase 1 and decreased free VEGF. Whether restoration of circulating VEGF can restore renal function and chronically decrease arterial pressure associated with placental ischemia remains unknown. We hypothesized that chronic infusion of VEGF(121) would attenuate hypertension, increase glomerular filtration rate, and reverse the endothelial dysfunction associated with chronic RUPP. VEGF(121) (at either 90 or 180 microg/kg per day) was administered for 5 days via osmotic minipump placed IP. Mean arterial pressure, renal function, and tissues were obtained on day 19 of pregnancy from RUPP+VEGF, RUPP, and normal pregnant dams. Mean arterial pressure was increased in the RUPP (131+/-3 mm Hg) compared with the normal pregnant (102+/-1 mm Hg) rats, and infusion of VEGF(121) resolved the hypertension (105+/-5 mm Hg). Glomerular filtration rate was decreased in the RUPP dams (1.5+/-0.3 mL/min) and restored to normal pregnant levels (3.1+/-0.5 mL/min) by VEGF(121) treatment (3.1+/-0.4 mL/min). Effective renal plasma flow, decreased by RUPP, was also increased by VEGF(121) infusion. Relaxation to acetylcholine was enhanced by the VEGF treatment (P<0.05). These data demonstrate that chronic infusion of VEGF(121) during late gestation restores glomerular filtration rate and endothelial function and reduces high blood pressure associated with placental ischemia. The present results suggest that VEGF(121) may be a candidate molecule for management of preeclampsia and its related complications.