Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia as placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and VEGF are both natural ligands for sFlt-1, VEGF also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to four groups: normal pregnant (NP) or RUPP ± infusion of rhPlGF (180 μg/kg/day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than NP rats. Infusion of rhPlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that rhPlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia.

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While epidemiological studies have repeatedly shown that overweight and obesity are associated with hypertension during pregnancy, the mechanisms linking these co-morbidities are not as explored. Reports show reduced levels of the anti-hypertensive and pregnancy-related factor, placental growth factor (PlGF), in obese hypertensive pregnant humans. We tested the hypothesis that obese hypertensive pregnant rats have reduced PlGF whereas increasing its levels reduces their blood pressure. We utilized a genetic model of obesity in rats having heterozygous deficiency of the melanocortin-4 receptor (MC4R-def) compared to wild-type lean controls. By gestational day 19, body mass (341±8 vs 311±7 g), periaortic adipose tissue (10.9±1.1 vs 8.2±0.5 mg), retroperitoneal adipose tissue (4.4±0.4 vs 2.5±0.2 g), circulating levels of leptin (10±1 vs 6±1 ng/mL), and mean arterial blood pressure (116±2 vs 105±2 mmHg) were greater (all P<0.05) in obese (N=17) compared to lean (N=14) pregnant rats. PlGF levels were lower (P<0.05) in serum (61±6 vs. 78±7 pg/mL) and secreted from placental (58±3 vs 71±3 pg/mg) and periaortic adipose tissue (7±1 vs 15±2 pg/mL) explants in obese compared to lean groups. PlGF secretion from retroperitoneal adipose tissue was similar between obese (78±10 pg/mL) and lean (62±12 pg/mL) groups. Vascular expression of the PlGF receptor, vascular endothelial growth factor receptor 1 (VEGFR1), was lower (P<0.05) in aortic tissue (832±60 vs 1106±91 pg/mg) but higher (P<0.05) in small mesenteric arteries (214±23 vs. 151±17 pg/mg) from the obese pregnant rats. Chronic administration of recombinant human (rh)PlGF (180 ug/kg per day) from gestational day 13-19 produced detectable levels of human PlGF in serum from both lean (33±4 pg/mL) and obese (43±4 pg/mL) pregnant rats and reduced (P<0.05) blood pressure in obese (102±3 mmHg) but not in lean (101±3 mmHg) groups. The treatment did not alter maternal body or fat masses or circulating leptin. In summary, PlGF is reduced in MC4R-def obese hypertensive pregnant rats, similar to findings in obese pregnant humans, whereas increasing the levels of PlGF reduced their hypertensive phenotype. Thus, treatment with rhPlGF may prove beneficial in attenuating blood pressure in obese hypertensive pregnancies.

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Preeclampsia (PE) is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Progress toward potential therapeutic targets has found that placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in human patients stimulates the release of hypertensive placental factors into the maternal circulation. For example, the antiangiogenic factor sFlt-1, which antagonizes and reduces bioavailable vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), is significantly elevated in PE patients and RUPP rats. It is clear that reductions in VEGF promote hypertension in RUPP rats as supplementation with recombinant VEGF at 180 ug/kg/day abolished the hypertension. However, it is unknown if reductions in PlGF levels also contribute to the hypertensive response. Thus, we tested the hypothesis that PlGF treatment would reduce placental ischemia-induced hypertension. On gestational day 14, Sprague Dawley rats were randomized to three groups: normal pregnant (NP, N=6), RUPP (N=5) and RUPP + 180 ug/kg/day PlGF (N=7). The rPlGF (AG31, a purified-recombinant human PlGF) was infused via i.p. osmotic minipump. Mean arterial blood pressure (MAP, carotid catheter) and pregnancy weights were assessed on day 19. MAP was significantly higher in RUPP than NP rats (123±4 vs. 104±1, P<0.05). PlGF reversed these levels to NP values (105±3, P<0.05 vs. RUPP). Placental weights (NP: 0.5±0.02; RUPP: 0.51±0.04; and RUPP+rPlGF: 0.5±0.05) and fetal weights (NP: 2.30±0.07; RUPP: 2.00±0.15; and RUPP+rPlGF: 2.09±0.07) were similar among all groups. The number of live fetuses was reduced in RUPP than NP rats (5±2 vs. 12±1, P<0.05) with a slight increase in the RUPP+rPlGF group (8±1). The number of fetal absorptions was increased in RUPP than NP rats (9±2 vs. 2±1, P<0.05) with a slight increase in the RUPP+rPlGF group (5±1). In conclusion, these data indicate that the reductions in PlGF that occur as a result of placental ischemia contribute to the development of maternal hypertension. Our novel finding that rPlGF abolishes placental ischemia-induced hypertension suggests a strong role and therapeutic potential for this growth factor in PE.

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