Placental Growth Factor Reduces Blood Pressure in a Uteroplacental Ischemia Model of Preeclampsia in Nonhuman Primates

Abstract

An imbalance in the angiogenesis axis during pregnancy manifests as clinical preeclampsia due to endothelial dysfunction. Circulating sFLT-1 (soluble fms-like tyrosine kinase 1) increases and PlGF (placental growth factor) reduces prior to and during disease. We investigated the clinical and biochemical effects of replenishing the reduced circulating PlGF with recombinant human PlGF (rhPlGF) and thus restoring the angiogenic balance. Hypertensive proteinuria was induced in a non-human primate (Papio hamadryas) by uterine artery ligation at 136 days gestation (of an 182 day pregnancy). Two weeks after uteroplacental ischemia (UPI), rhPlGF (rhPlGF, n=3) or normal saline (control, n=4) was administered by subcutaneous injection (100μg/kg/day) for 5 days. Blood pressure (BP) was monitored by intra-arterial radiotelemetry, sFLT-1 and PlGF by ELISA. UPI resulted in experimental preeclampsia evidenced by increased BP, proteinuria and endotheliosis on renal biopsy and elevated sFLT-1. PlGF significantly reduced after UPI. rhPlGF reduced SBP in the treated group (-5.2mmHg+0.8mmHg;from 132.6+6.6mmHg to 124.1+7.6mmHg) compared to an increase in SBP in controls (6.5mmHg+3mmHg; from 131.3+1.5mmHg to 138.6+1.5mmHg). Proteinuria reduced in the treated group (-72.7±55.7mg/mmol) but increased in the control group. Circulating sFLT-1 was not affected by the administration of PlGF, however a reduction in placental sFLT-1 mRNA expression was demonstrated. There was no significant difference in the weights or lengths of the neonates in the rhPlGF or control group, however, this study was not designed to assess fetal safety or outcomes. Increasing circulating PlGF by the administration of rhPlGF improves clinical parameters in a primate animal model of experimental preeclampsia.

Placental Growth Factor

“…When it comes to pregnancy and preeclampsia research, studies in nonhuman primates represent an important translational link. As pointed out by Makris et al, 4 although dissimilarities exist between human and nonhuman primates when it comes to the establishment of pregnancy including placenta pathology, mechanistic studies investigating the pathogenesis of preeclampsia in nonhuman primates offer advantages over other species (mice, rats, and sheep) that are commonly utilized in this field. For instance, the placenta is hemochorial and the implantation is essentially similar to that observed in humans.…”

“…Much work remains to be done. Although the findings of Makris et al 4 provide new insights into the therapeutic potential of targeting PlGF to treat preeclampsia, at the same time they raise new questions that will require interrogation in future studies before such treatments could be introduced to the clinic. In particular, although this study investigated the effects of recombinant human PlGF on the mother, a limitation of the work was that fetal wellbeing was not assessed as an end point.…”

“…The investigators attribute this to partial reperfusion of the ischemic placenta based on the observations of others that increases in PlGF correlate to increased placental perfusion. 9 Remarkably, Makris et al 4 also demonstrated that administration of recombinant human PlGF reduced arterial pressure and proteinuria and improved endotheliosis (as observed on renal biopsy) in their baboon model of preeclampsia (Figure). This provides strong evidence that targeting the angiogenic imbalance in preeclampsia by increasing PlGF levels can improve endothelial function.…”

“…In the current issue of Hypertension, the study by Makris et al 4 takes a vital step toward confirming the potent angiogenic factor, placental growth factor (PlGF), as a suitable therapeutic target to combat preeclampsia. Certainly, extensive research during the past few decades has led to the recognition that maternal endothelial abnormalities underlie many of the clinical manifestations of preeclampsia.…”

“…4 The first key finding of their study was that induction of uteroplacental ischemia produced a decrease in circulating PlGF levels; thus providing direct evidence for a causal relationship between reduced placental perfusion and modulation of angiogenic balance in the clinical manifestation of disease. However, it was noted that PlGF levels rose back to baseline levels after 10 days of uteroplacental ischemia.…”