Tumor Necrosis Factor-alpha Blockade Improves Uterine Artery Resistance, Maternal Blood Pressure, and Fetal Growth in Placental Ischemic Rats

Travis, Olivia K.; Tardo, Geilda A.; Giachelli, Chelsea; Siddiq, Shani; Nguyen, Henry T.; Crosby, Madison T.; Johnson, Tyler D.; Brown, Adam R.; Cornelius, Denise C.

doi:10.1016/j.preghy.2021.05.002

Cited by 12 publications

(8 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The RUPP model has been widely used to investigate the therapeutic effects of various drugs on insufficient placental perfusion. In RUPP rodents, the number and size of uterine Etanercept, IL-17RC, and MZe786, have been found to significantly mitigate FGR in RUPP animals [92][93][94][95]. Because ADE101 could completely reverse the placental ischemia-induced hypertension, and significantly improve fetus/placenta development in RUPP rats, it could be among the most promising candidates for protecting against placental ischemia-associated pathology or preeclampsia.…”

Section: Discussionmentioning

confidence: 99%

“…In RUPP rodents, the number and size of uterine spiral arterioles decreases and the expression of MMP-2 and MMP-9 in uterus and uterine arteries is lower. Several therapeutic candidates, including 17-alpha-hydroxyprogesterone, pravastatin, sildenafil, interleukin (IL)-10, vitamin D, placental growth factor, relaxin, liraglutide, sonic hedgehog protein, low dose IL-2, IL-25, an angiotensin II type 1 receptor autoantibody blockade peptide, Etanercept, a hydrogen sulfide releasing molecule MZe786, l -(+)-ergothioneine, a soluble IL-17 receptor IL-17RC, and apelin, as well as interferon γ neutralization, have been found to reduce hypertension in RUPP animals to varying degrees [78–96]. However, only a few candidates, such as IL-25, Etanercept, IL-17RC, and MZe786, have been found to significantly mitigate FGR in RUPP animals [92–95].…”

Section: Discussionmentioning

confidence: 99%

“…The RUPP model is characterized by placental ischemia, maternal endothelial dysfunction, and increased vascular resistance and stiffness [75][76][77]. It was used to evaluate the translational potential of various therapeutic candidates on pregnancy-associated hypertension and fetal growth restriction [78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96]. Although this rodent model is not ideal for modeling preeclampsia in humans, this proof-of-concept study demonstrated that ADE101 could be a promising candidate for improving vascular homeostasis in patients with pregnancy-associated hypertension and fetal growth restriction.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats

Chang

Cai²,

Hsu³

2023

Journal of Hypertension

View full text Add to dashboard Cite

Objective(s):Preeclampsia is a heterogeneous hypertensive disorder of pregnancy. It affects multiorgans and may lead to fetal growth restriction, organ failure, seizure, and maternal death. Unfortunately, current treatments are ineffective at delaying the progression of preeclampsia even for a few days. Clinicians are often forced to deliver preterm fetus if severe preeclampsia occurred early during pregnancy, leading to premature birth-associated complications. Preeclampsia has been associated with defects at the maternal–fetal interface and maternal vascular dysfunction. Of interest, the adrenomedullin peptide and its cognate receptors, calcitonin receptor-like receptor (CLR)/ receptor activity-modifying protein (RAMP) receptor complexes, have been shown to be important regulators of cardiovascular adaptation and feto-placental development during pregnancy. Although the exact role of adrenomedullin-CLR/RAMP signaling in different feto-maternal compartments during pregnancy and how adrenomedullin expression affects preeclampsia development remains to be clarified, we hypothesized that the sustained activation of CLR/RAMP receptors could be a promising strategy to mitigate placental ischemia-associated vascular dysfunction and fetal growth restriction under preeclampsia-like conditionsMethods:To explore this possibility, we have developed a stable adrenomedullin analog, ADE101, and investigated its effects on human lymphatic microvascular endothelial (HLME) cell proliferation, hemodynamics, and pregnancy outcomes in pregnant rats with reduced uteroplacental perfusion pressure (RUPP) induced by clipping of uterine arteries on gestation day 14Results:The ADE101 analog has a potent effect on CLR/RAMP2 receptor activation, and an enhanced stimulatory effect on HLME cell proliferation compared to wild-type peptides. ADE101 also exhibits a lasting effect on hemodynamics in normal and hypertensive rats. In addition, studies using the RUPP model showed that ADE101 significantly reduces placental ischemia-induced hypertension and fetal growth restriction in a dose-dependent manner. Infusion of ADE101 increased the weight of fetuses and placentas in RUPP animals to 252% and 202% of that of RUPP controls, respectively.Conclusions:These data suggested that long-acting adrenomedullin analog could be useful for quenching hypertension as well as the vascular ischemia-associated organ damages in preeclamptic patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats

Chang

Cai²,

Hsu³

2023

Journal of Hypertension

View full text Add to dashboard Cite

show abstract

“…TNF-α alone induces symptoms of PE in animal models including hypertension, FGR, oxidative stress, Endothelin-1 and AT1-AA in pregnancy (LaMarca et al, 2005;Jayaram et al, 2021). But inhibition of TNF-α in multiple models of PE can attenuate hypertension, maternal inflammation, and fetal morbidity (Irani et al, 2010;Travis et al, 2021). PE patients also have increased Th17s and IL-17 (Ding et al, 2019;El Shahaway et al, 2019).…”

Section: Soluble Immune Factors In Preeclampsiamentioning

confidence: 99%

Setting a stage: Inflammation during preeclampsia and postpartum

2023

View full text Add to dashboard Cite

Preeclampsia (PE) is a leading cause of maternal and fetal mortality worldwide. The immune system plays a critical role in normal pregnancy progression; however, inappropriate inflammatory responses have been consistently linked with PE pathophysiology. This inflammatory phenotype consists of activation of the innate immune system, adaptive immune system, and increased inflammatory mediators in circulation. Moreover, recent studies have shown that the inflammatory profile seen in PE persists into the postpartum period. This manuscript aims to highlight recent advances in research relating to inflammation in PE as well as the inflammation that persists postpartum in women after a PE pregnancy. With the advent of the COVID-19 pandemic, there has been an increase in obstetric disorders associated with COVID-19 infection during pregnancy. This manuscript also aims to shed light on the relationship between COVID-19 infection during pregnancy and the increased incidence of PE in these women.

show abstract

“…Pregnant mice exposed to chronic intermittent hypoxia display uterine vascular dysfunction as evidenced by reduced endothelium-dependent vasodilatation and enhanced vasoconstriction, which are associated with increased plasma TNFα and sFlt-1 [302]. In two rat models of preeclamp-sia, administration of the TNFα inhibitor etanercept restores uterine vascular function by increasing endothelium-dependent vasorelaxation to acetylcholine and decreasing vasoconstriction to norepinephrine in uterine arteries of RUPP rats and stroke-prone spontaneously hypertensive rats, resulting in reduced uterine vascular resistance [303,304].…”

Section: Inflammationmentioning

confidence: 99%

Uteroplacental Circulation in Normal Pregnancy and Preeclampsia: Functional Adaptation and Maladaptation

Zhang

2021

IJMS

View full text Add to dashboard Cite

Uteroplacental blood flow increases as pregnancy advances. Adequate supply of nutrients and oxygen carried by uteroplacental blood flow is essential for the well-being of the mother and growth/development of the fetus. The uteroplacental hemodynamic change is accomplished primarily through uterine vascular adaptation, involving hormonal regulation of myogenic tone, vasoreactivity, release of vasoactive factors and others, in addition to the remodeling of spiral arteries. In preeclampsia, hormonal and angiogenic imbalance, proinflammatory cytokines and autoantibodies cause dysfunction of both endothelium and vascular smooth muscle cells of the uteroplacental vasculature. Consequently, the vascular dysfunction leads to increased vascular resistance and reduced blood flow in the uteroplacental circulation. In this article, the (mal)adaptation of uteroplacental vascular function in normal pregnancy and preeclampsia and underlying mechanisms are reviewed.

show abstract

Tumor Necrosis Factor-alpha Blockade Improves Uterine Artery Resistance, Maternal Blood Pressure, and Fetal Growth in Placental Ischemic Rats

Cited by 12 publications

References 70 publications

Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats

Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats

Setting a stage: Inflammation during preeclampsia and postpartum

Uteroplacental Circulation in Normal Pregnancy and Preeclampsia: Functional Adaptation and Maladaptation

Contact Info

Product

Resources

About