Placental growth factor administration prevents hypertension, increased sFlt‐1 levels and reduced glomerular filtration rate responses to placental ischemia

Abstract

Preeclampsia is a pregnancy‐specific disorder noted by new‐onset hypertension in the mother accompanied by a variety of other cardiovascular disturbances. Unfortunately, the most effective treatment is early delivery of the fetus and the ischemic placenta. Progress toward treatment has found that placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in human patients stimulates release of hypertensive placental factors into the maternal circulation. The anti‐angiogenic factor sFlt‐1, which antagonizes and reduces bioavailable vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), is elevated in RUPP rats and preeclamptic patients. Although PlGF and VEGF are both natural ligands for sFlt‐1, VEGF also binds with high‐affinity to Flk1 (VEGFR2) causing side‐effects related to excess Flk1 signaling including edema. In contrast, PlGF is specific for sFlt‐1. Thus, we tested the hypothesis that PlGF treatment would reduce placental ischemia‐induced hypertension without any adverse consequences to the mother or fetus. On gestational day 14, Sprague Dawley rats were randomized in to three groups: normal pregnant (NP, N=9), RUPP (N=11) and RUPP + 180 μg/kg/day PlGF (N=6). The rhPlGF (AG31, a purified‐recombinant human PlGF) was infused via intraperitoneal osmotic minipump. Mean arterial blood pressure (MAP, carotid catheter); glomerular filtration rate (GFR); placental and fetal weights; and plasma sFlt‐1 levels were assessed on day 19. Data is mean ± standard error. MAP (NP: 104±1 vs. RUPP: 123±4 mmHg) and plasma sFlt‐1 levels (NP: 26±12 vs. RUPP: 660±150 ng/mL) were significantly higher (P<0.05) in the RUPP rats. Whereas, total placental weights (NP: 6.1±0.6 vs. RUPP: 2.1±0.3 g); total fetal weights (NP: 26.1±2.5 vs. RUPP: 9.2±1.3 g); and GFR (NP: 4.2±0.4 vs. RUPP: 3.8±0.3 mL/min) were significantly reduced (P<0.05) in the RUPP rats. Treatment of RUPP rats with rhPlGF significantly reduced (P<0.05) MAP (105±3 mmHg) and sFlt‐1 levels (79±17 ng/mL); did not alter placental weights (2.6±0.5 g) or fetal weights (12.6±2.3 g); but significantly elevated (P<0.05) GFR (3.0±0.1) compared to untreated RUPP rats. There were no major adverse maternal consequences such as signs of edema with rhPlGF. These data indicate that the increased sFlt‐1 and reduced PlGF known to occur as a result of placental ischemia contribute to the development of maternal hypertension. In conclusion, our finding that rhPlGF prevents placental ischemia‐induced hypertension and restores renal hemodynamics suggests a strong therapeutic potential for this growth factor in preeclampsia by interfering in anti‐angiogenic pathways.Support or Funding InformationSBIR 1R43HD082657, T32HL105324‐01, P01HL051971