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

Abstract

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. Key Words: preeclampsia Ⅲ gestation Ⅲ VEGF Ⅲ blood pressure Ⅲ angiogenic P reeclampsia is a major obstetric problem that affects Ϸ5% of all pregnancies and is a significant source of maternal and neonatal morbidity and mortality. 1 Moreover, the incidence of preeclampsia has seen a 40% increase in recent years. 2 Although the preeclamptic syndrome has been well characterized, and many studies indicate that hypertension, proteinuria, endothelial cell dysfunction, and insufficient placentation are key features of this disorder, 3,4 the underlying pathophysiological mechanisms of this disorder remain unclear.Recent studies have established the existence of an imbalance between proangiogenic and antiangiogenic factors, such as vascular endothelial growth factor (VEGF), placental growth factor, and soluble fms-like tyrosine kinase 1 (sFlt-1) in preeclamptic women. 5-10 Moreover, findings from several clinical studies suggest that alterations in circulating sFlt-1 concentrations may presage the clinical onset of preeclamptic symptoms. 5,[11][12][13] Viewed in concert with recent experimental studies in animals, it appears that this dysregulation of angiogenic factors may play a key role in the pathogenesis of preeclampsia. 9,10,14 -19 Although the mechanisms underlying the overexpression of antiangiogenic factors, such as sFlt-1, are currently unresolved, in vitro and in vivo evidence suggest that placental hypoxia/ischemia may initiate this imbalance of angiogenic factors. 14,16,20 Both Gilbert et al 14 and Makris et al 16 have shown in vivo that chronic placental ischemia results in elevated circulating levels of sFlt-1 and hypertension. In addition, previous studies have shown that reduced uterine perfusion pressure (RUPP) is associated with decreased

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

“…We found that spiking the ELISA standard curves with ELP‐VEGF reduced the signal, suggesting that ELP‐VEGF might bind the Flt‐1 in the assay and prevent binding of 1 or both antibodies, thus confirming this as an assay for free sFlt‐1. Again, RUPP surgery resulted in a significant increase in free plasma sFlt‐1 (Figure 4C), consistent with previous reports 32, 36, 53, 56, 58, 63, 68. In contrast to the Western blot data, the ELISA data showed that ELP‐VEGF‐treated rats (both sham and RUPP surgical groups) had markedly reduced free sFlt‐1 levels (Figure 4C).…”

“…These bands correspond to the report of Rajakumar,67 who describes sFlt‐1 bands of 145, 100, and 60 kDa in plasma from preeclamptic patients, though considerable species and glycosylation variation could exist. The RUPP surgery leads to a significant increase in plasma sFlt‐1, as has previously been reported 32, 36, 53, 56, 58, 68. This was confirmed in a separate cohort of rats, treated entirely independently with the sham or RUPP surgeries, and analyzed in a separate Western blot (Figure S1).…”

“…Studies using viral overexpression33, 57, 59, 60, 61 or direct infusion of sFlt‐132, 55, 62, 63 have demonstrated a critical role for this anti‐angiogenic factor for induction of hypertension and renal damage during pregnancy. Previous studies using exogenous VEGF infusion have reported reduced circulating sFlt‐1 levels 36, 64. However, induction of local VEGF expression in the maternal decidua was shown to actually promote increased placental sFlt‐1 expression in the cytotrophoblasts,65 suggesting a protective role for placental sFlt‐1 against maternal overproduction of VEGF 66.…”

“…This directive applies especially to VEGF supplementation in the gravid female because of a myriad of adverse fetal effects from VEGF overexposure that have been observed in animal models 81, 82, 83, 84, 85, 86. Previous studies using free VEGF‐A isoforms, including VEGF‐A 165 87, 88, 89 and VEGF‐A 121 ,36, 64, 90, 91 have demonstrated therapeutic efficacy in treating the maternal syndrome of preeclampsia. In these previous studies, VEGF was administered in vitro,88 by chronic infusion,36, 64 or via adenoviral vector overexpression 31, 87, 89, 90, 91.…”

“…Strategies to target sFlt‐1 have shown preclinical efficacy in combating preeclampsia in rodent models 36. These include administration of exogenous growth factors that bind Flt‐1 and sFlt‐1, including VEGF and placental growth factor,37, 38 thereby sequestering sFlt‐1 and restoring angiogenic balance and bioavailable VEGF.…”