eNOS Deficiency Acts through Endothelin to Aggravate sFlt-1–Induced Pre-Eclampsia–Like Phenotype

Abstract

Excess soluble fms-like tyrosine kinase 1 (sFlt-1) of vascular endothelial growth factor receptor 1 secreted from the placenta causes pre-eclampsia-like features by antagonizing vascular endothelial growth factor signaling, which can lead to reduced endothelial nitric oxide synthase (eNOS) activity; the effect of this concomitant decrease in eNOS activity is unknown. We tested whether the decrease in nitric oxide occurring in female mice lacking eNOS aggravates the pre-eclampsia-like phenotype induced by increased sFlt-1. Untreated eNOS-deficient female mice had higher BP than wild-type mice. Adenovirus-mediated overexpression of sFlt-1 increased systolic BP by approximately 27 mmHg and led to severe loss of fenestration of glomerular capillary endothelial cells in both eNOS-deficient and wild-type mice. However, only the eNOS-deficient sFlt-1 mice exhibited severe foot process effacement. Compared with wild-type sFlt-1 mice, eNOS-deficient sFlt-1 mice also showed markedly higher urinary albumin excretion (467674 versus 174623 mg/d), lower creatinine clearance (126629 versus 452663 ml/min), and more severe endotheliosis. Expression of preproendothelin-1 (ET-1) and its ET A receptor in the kidney was higher in eNOS-deficient sFlt-1 mice than in wild-type sFlt-1 mice. Furthermore, the selective ET A receptor antagonist ambrisentan attenuated the increases in BP and urinary albumin excretion and ameliorated endotheliosis in both wild-type and eNOS-deficient sFlt-1 mice. Ambrisentan improved creatinine clearance and podocyte effacement in eNOS-deficient sFlt-1 mice. In conclusion, reduced maternal eNOS/nitric oxide exacerbates the sFlt1-related pre-eclampsia-like phenotype through activation of the endothelin system. Pre-eclampsia is a pregnancy-related disease characterized by high BP and proteinuria, and affects 3%-5% of all pregnancies. 1,2 Although the etiology of pre-eclampsia is not fully understood, it is widely accepted that placental hypoxia/ischemia increases the production by the placenta of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin, and likely other factors. 1 Increased sFlt-1 is recognized as one of the most important causal factors for maternal symptoms of pre-eclampsia. 1 sFlt-1 is a splice variant of vascular endothelial growth factor (VEGF) receptor-1 that lacks the cytoplasmic and transmembrane domains, but retains the ligandbinding domain. sFlt-1 decreases the chance of VEGF binding to its signaling receptor, and reduces the phosphorylation of Ser 1177 of endothelial nitric oxide synthase (eNOS) by VEGF and the activity of eNOS. 3 Plasma concentration of sFlt-1 is

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

“…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.…”

“…Unable to meet the metabolic demands of the developing fetus because of this compromised arterial blood supply, the placenta enters a chronically hypoxic/ischemic state,27 which activates pathways that increase the production of inflammatory cytokines,20 reactive oxygen species,28 and angiogenic imbalance factors including the soluble form of the vascular endothelial growth factor (VEGF) receptor Flt‐1 (sFlt‐1),29 all of which lead to systemic endothelial dysfunction that is manifested as hypertension 30. Among these, sFlt‐1 has been implicated as a major driver of the preeclampsia syndrome because of its high levels in the plasma of preeclamptic mothers31 and the fact that exogenously administered sFlt‐1 induces a preeclampsia‐like syndrome in pregnant rodents 32, 33, 34, 35…”

Hydrogen Sulfide Attenuates sFlt1-Induced Hypertension and Renal Damage by Upregulating Vascular Endothelial Growth Factor

“…We also do not know whether H 2 S will downregulate endothelin synthesis, which was recently shown to be a key downstream signaling pathway that mediates sFlt1-induced vascular disease. 44 Finally, H 2 S is known for its antioxidative and ischemia/hypoxia protective features. 45 Because massive sFlt1 production is thought to be secondary to hypoxia, we suggest that cytoprotection could be another protective effect of H 2 S in the sFlt1-induced phenotype.…”

The Robyn Barst Memorial Lecture: Differences between the Fetal, Newborn, and Adult Pulmonary Circulations: Relevance for Age‐Specific Therapies (2013 Grover Conference Series)

“…96,97 Several recent studies have shown that preeclampsia is a risk factor for BPD and PVD 98 and that disruption of the VEGF and other vascular signaling pathways, including soluble endoglin associated with preeclampsia, may contribute to impaired angiogenesis in preterm infants born to these mothers. [98][99][100][101] Placental overproduction of soluble VEGF receptor-1 (soluble fms-like tyrosine kinase-1 [sFlt-1]), which inhibits VEGF signaling through trapping free VEGF, 102 causes maternal endothelial dysfunction and plays a central role in the pathogenesis of preeclampsia. 99,103,104 Intraamniotic sFlt-1 administration during late gestation impairs lung VEGF signaling and increases apoptosis of endothelial cells in newborn rats, which is followed by reductions in alveolarization and vascular growth, along with biventricular hypertrophy during infancy.…”