Recombinant vascular endothelial growth factor 121 infusion lowers blood pressure and improves renal function in rats with placentalischemia-induced hypertension

Abstract

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.

Figure 1

Mean arterial pressure (MAP) was increased (P<0.05) in the reduced uterine perfusion pressure (RUPP) compared to normal pregnant+vehicle (NP) rats on day 19 of gestation (term = 21 days). VEGF₁₂₁ infusion reduced MAP in the RUPP+VEGF₁₂₁ rats in a dose dependent manner with the high dose treatment abrogating the placental ischemia induced hypertension (P<0.05, RUPP+VEGF₁₂₁ high dose vs. RUPP).

Figure 2

Glomerular filtration rate (GFR; Figure 2, panel A) and effective renal plasma flow (ERPF; Figure 2, panel B) was decreased (P<0.05) in the reduced uterine perfusion pressure (RUPP) compared to normal pregnant (NP) rats on day 19 of gestation (term = 21 days). VEGF₁₂₁ infusion increased GFR (panel A) and ERPF (panel B) in the RUPP+VEGF₁₂₁ rats in a dose dependent manner with the high dose treatment abrogating the placental ischemia-induced decline in renal function (P<0.05, RUPP+VEGF₁₂₁ high dose vs. RUPP).

Figure 3

Endothelial dependent vascular relaxation of the carotid artery (preconstricted to U46619) to acetylcholine (ACh) was enhanced by chronic infusion of VEGF₁₂₁ (180μg/kg) for five days to reduced uterine perfusion pressure (RUPP) rats when compared to normal pregnant + vehicle control (NP) rats. The log EC50 for ACh was decreased in the RUPP+VEGF₁₂₁ compared to RUPP rats (log -6.998 vs. -10.29; P<0.05). *Indicates significantly different than RUPP treated group.

Figure 4

Reduced uterine perfusion pressure (RUPP) resulted in a decrease of VEGF and an increase of sFlt-1 when compared to normal pregnant+vehicle (NP) rats at day 19 of pregnancy (Figure 4A and B). Infusion of VEGF₁₂₁ restored circulating VEGF to NP levels (Figure 4A). Interestingly, chronic infusion of VEGF decreased plasma sFlt-1 levels in the RUPP+VEGF₁₂₁ group to that of NP rats (Figure 4B).

Figure 5

Panel A illustrates that reduced uterine perfusion pressure (RUPP) fetuses were smaller than the normal pregnant+vehicle (NP) fetuses (P<0.05). Chronic infusion of VEGF₁₂₁ at 90 μg/kg (low dose) in the RUPP+VEGF₁₂₁ group resulted in fetuses that were not smaller than the NP groups. High dose infusion of VEGF₁₂₁ (180 μg/kg) into RUPP rats had no effect on fetal growth. Placental size was not altered by RUPP or VEGF₁₂₁ infusion in the present study (Panel B).