Interactions between the complement and endothelin systems in normal pregnancy and following placental ischemia

Regal, Jean F.; Lund, Jenna M.; Wing, Cameron R.; Root, Kate M.; McCutcheon, Luke; Bemis, Lynne T.; Gilbert, Jeffrey S.; Fleming, Sherry D.

doi:10.1016/j.molimm.2019.06.015

Cited by 12 publications

(13 citation statements)

References 47 publications

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“…In addition to the previous study, they hypothesized that complement activation following placental ischemia leads to activation of the endothelin pathway which triggers hypertension and FGR (43). However, they suggested a complex interaction of the endothelin and complement system in normal pregnancies (43).…”

Section: Inhibition Of the Complement System In Preeclamptic Animal Modelsmentioning

confidence: 88%

Dysregulation of Complement Activation and Placental Dysfunction: A Potential Target to Treat Preeclampsia?

et al. 2020

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Preeclampsia is one of the leading causes of maternal and neonatal mortality and morbidity worldwide, affecting 2-8% of all pregnancies. Studies suggest a link between complement activation and preeclampsia. The complement system plays an essential role in the innate immunity, leading to opsonization, inflammation, and elimination of potential pathogens. The complement system also provides a link between innate and adaptive immunity and clearance of immune complexes and apoptotic cells. During pregnancy there is increased activity of the complement system systemically. However, locally at the placenta, complement inhibition is crucial for the maintenance of a normal pregnancy. Inappropriate or excessive activation of the complement system at the placenta is likely involved in placental dysfunction, and is in turn associated with pregnancy complications like preeclampsia. Therefore, modulation of the complement system could be a potential therapeutic target to prevent pregnancy complications such as preeclampsia. This review, based on a systematic literature search, gives an overview of the complement system and its activation locally in the placenta and systemically during healthy pregnancies and during complicated pregnancies, with a focus on preeclampsia. Furthermore, this review describes results of animal and human studies with a focus on the complement system in pregnancy, and the role of the complement system in placental dysfunction. Various clinical and animal studies provide evidence that dysregulation of the complement system is associated with placental dysfunction and therefore with preeclampsia. Several drugs are used for prevention and treatment of preeclampsia in humans and animal models, and some of these drugs work through complement modulation. Therefore, this review further discusses these studies examining pharmaceutical interventions as treatment for preeclampsia. These observations will help direct research to generate new target options for prevention and treatment of preeclampsia, which include direct and indirect modulation of the complement system.

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Section: Inhibition Of the Complement System In Preeclamptic Animal Modelsmentioning

confidence: 88%

Dysregulation of Complement Activation and Placental Dysfunction: A Potential Target to Treat Preeclampsia?

et al. 2020

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“…Jeoung et al hypothesized that endothelins are required in the oviduct to facilitate early embryonic development, and they demonstrated that antagonism of endothelin resulted in a reduction in the number of two cell embryos developing ( 58 ). Our studies with the endothelin 1 antagonist, atrasentan, in the third trimester of rat gestation demonstrated that this inhibitor down-regulated the message for complement regulators in the placenta, suggesting that endothelin was important for controlling complement activation by influencing the expression of complement regulators ( 59 ). Thus, endothelin in normal embryonic development may ensure up-regulation of expression of complement system regulators to protect the embryo.…”

Section: Role Of Complement In Pre-implantationmentioning

confidence: 90%

Essential Role of Complement in Pregnancy: From Implantation to Parturition and Beyond

et al. 2020

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The complement cascade was identified over 100 years ago, yet investigation of its role in pregnancy remains an area of intense research. Complement inhibitors at the maternal-fetal interface prevent inappropriate complement activation to protect the fetus. However, this versatile proteolytic cascade also favorably influences numerous stages of pregnancy, including implantation, fetal development, and labor. Inappropriate complement activation in pregnancy can have adverse lifelong sequelae for both mother and child. This review summarizes the current understanding of complement activation during all stages of pregnancy. In addition, consequences of complement dysregulation during adverse pregnancy outcomes from miscarriage, preeclampsia, and pre-term birth are examined. Finally, future research directions into complement activation during pregnancy are considered.

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“…It has been postulated that C activation following placental ischemia may induce hypertension and impair fetal growth via the endothelin pathway ( 35 ). Analysis of C activation products in patients with pre-eclampsia has revealed increased serum levels of C3a, C5a, and SC5b-9 ( 16 , 36 , 37 ) and C activation products have also been detected in the urine of patients with a severe form of the disease as a result of C-mediated renal injury ( 38 ).…”

Section: Complement and Adverse Pregnancy Outcomementioning

confidence: 99%

The Complement System in the Pathophysiology of Pregnancy and in Systemic Autoimmune Rheumatic Diseases During Pregnancy

et al. 2020

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The complement system plays a double role in pregnancy exerting both protective and damaging effects at placental level. Complement activation at fetal-maternal interface participates in protection against infectious agents and helps remove apoptotic and necrotic cells. Locally synthesized C1q contributes to the physiologic vascular remodeling of spiral arteries characterized by loss of smooth muscle cells and transformation into large dilated vessels. Complement activation triggered by the inflammatory process induced by embryo implantation can damage trophoblast and other decidual cells that may lead to pregnancy complications if the cells are not protected by the complement regulators CD55, CD46, and CD59 expressed on cell surface. However, uncontrolled complement activation induces placental alterations resulting in adverse pregnancy outcomes. This may occur in pathological conditions characterized by placental localization of complement fixing antibodies directed against beta2-glycoprotein 1, as in patients with anti-phospholipid syndrome, or circulating immune complexes deposited in placenta, as in patients with systemic lupus erythematosus. In other diseases, such as preeclampsia, the mechanism of complement activation responsible for complement deposits in placenta is unclear. Conflicting results have been reported on the relevance of complement assays as diagnostic and prognostic tools to assess complement involvement in pregnant patients with these disorders.

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Interactions between the complement and endothelin systems in normal pregnancy and following placental ischemia

Cited by 12 publications

References 47 publications

Dysregulation of Complement Activation and Placental Dysfunction: A Potential Target to Treat Preeclampsia?

Dysregulation of Complement Activation and Placental Dysfunction: A Potential Target to Treat Preeclampsia?

Essential Role of Complement in Pregnancy: From Implantation to Parturition and Beyond

The Complement System in the Pathophysiology of Pregnancy and in Systemic Autoimmune Rheumatic Diseases During Pregnancy

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