Differential Effects of Complement Activation Products C3a and C5a on Cardiovascular Function in Hypertensive Pregnant Rats

Lillegard, Kathryn E; Loeks-Johnson, Alex C.; Opacich, Jonathan; Peterson, Jillian K.; Bauer, Ashley J.; Elmquist, Barbara J.; Regal, Ronald R.; Gilbert, Jeffrey S.; Regal, Jean F.

doi:10.1124/jpet.114.218123

Cited by 31 publications

(47 citation statements)

References 48 publications

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“…Since C3a and C5a anaphylatoxins have long been known to have vasoactive properties, the effect of small molecule antagonists of the C3a and C5a receptors were used to determine the important products of complement activation. Both the C3a and C5a receptor antagonists attenuated placental ischemia induced hypertension [89]. However, they differentially affected the increased heart rate and endothelial dysfunction indicating mechanistic differences in their ability to attenuate the hypertension.…”

Section: The Complement System In Stage 2 Of Preeclampsiamentioning

confidence: 99%

The Complement System and Preeclampsia

2017

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Purpose of review Preeclampsia affects 3–4% of pregnancies with few treatment options to reduce maternal and fetal harm. Recent evidence that targeting the complement system may be an effective therapeutic strategy in prevention or treatment of preeclampsia will be reviewed. Recent findings Studies in humans confirm the safety and efficacy of C5 blockade in complement-mediated disorders of pregnancy, including preeclampsia. Animal models mimic the placental abnormalities, and/or the maternal symptoms, which characterize preeclampsia. These models in mouse and rat have defined a role for complement and its regulators in placental dysfunction, hypertension, proteinuria, endothelial dysfunction, fetal growth restriction and angiogenic imbalance, thus informing future human studies. Summary Targeting excessive complement activation, particularly the terminal complement complex (C5b-9) and C5a may be an effective strategy to prolong pregnancy in women with preeclampsia. Continued research is needed to identify the initiator(s) of activation, the pathways involved and the key component(s) in the pathophysiology to allow development of safe and effective therapeutics to target complement without compromising its role in homeostasis and host defense.

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Section: The Complement System In Stage 2 Of Preeclampsiamentioning

confidence: 99%

The Complement System and Preeclampsia

2017

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“…Chronic placental ischemia in the RUPP model results in increased blood pressure in the mother, fetal growth restriction and complement activation as indicated by generation of C3a (Lillegard et al, 2013; Lillegard et al, 2014). As we have reported, this model also manifests other signs of preeclampsia including angiogenic imbalance with decreased vascular endothelial growth factor (VEGF) and increased soluble VEGF receptor (sFlt-1) (Bauer et al, 2013), though the validity of the VEGF and sFlt-1 assays in the rat have been questioned (Weissgerber et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Role of IgM and angiotensin II Type I receptor autoantibodies in local complement activation in placental ischemia-induced hypertension in the rat

Regal

Strehlke

Peterson

et al. 2016

Molecular Immunology

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Preeclampsia is characterized by development of hypertension during pregnancy and reduced placental perfusion. Previous studies in a rat model of placental ischemia-induced hypertension demonstrated that inhibiting complement activation attenuated increased maternal blood pressure with C3a and C5a identified as the important products of complement activation. Given that in other forms of ischemia both natural IgM and antigen antibody complexes initiate complement activation, we hypothesized that placental ischemia exposes neoepitopes recognized by IgM to cause local complement activation and hypertension. Alternatively, we postulated that autoantibody to angiotensin II Type 1 receptor (AT1-AA) interacts with AT1 receptors to cause complement activation. Since complement activation occurs in kidney and placenta in preeclampsia, we used immunohistochemistry to determine IgM deposition and local complement activation in each organ (C3 deposition), and quantitative real-time polymerase chain reaction (qRT-PCR) to quantitate mRNA for endogenous regulators of complement activation CD55, CD59 and Complement receptor 1-related gene/protein y (Crry). On gestation day (GD)14.5, timed pregnant Sprague Dawley rats underwent Sham surgery or placement of clips on inferior abdominal aorta and ovarian arteries to create placental ischemia using the reduced utero-placental perfusion pressure (RUPP) model. As previously reported, RUPP surgery increased mean arterial pressure and circulating C3a on GD19.5. In placenta, IgM and C3 deposition increased, whereas mRNA for complement regulators Crry and CD59 decreased along with Crry protein in RUPP compared to Sham treated animals. In kidney, IgM deposition increased in animals subjected to RUPP vs Sham surgery without a significant change in C3 deposition and coincident with an increase in mRNA for CD55 and CD59. The AT1 receptor antagonist losartan prevents placental ischemia-induced hypertension as well as AT1-AA interaction with AT1 receptors. However, losartan did not attenuate complement activation as measured by circulating C3a or placental C3 deposition. Importantly, our studies indicate that following placental ischemia, complement activation is not due to AT1-AA but is associated with IgM deposition. These studies suggest a role for natural antibodies interacting with placental ischemia-induced neoepitopes to activate complement and contribute to hypertension.

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“…Hypertension was induced in pregnant rats using the reduced uterine perfusion pressure (RUPP) model, and the animals were treated daily with the C5a receptor antagonist (C5aRA), PMX51 (acetyl-F-[Orn-P-(D-Cha)-WR]), the C3a receptor antagonist (C3aRA), SB290157 (N2-[(2,2-diphenylethoxy) acetyl]-L-arginine) on gestational days 14-18. Both C3aRA and C5aRA partially reversed hypertension on gestational day 19, while only the C5aRA lowered tachycardia and attenuated the impaired endothelium-dependent relaxation in the mesenteric artery (25). However, neither antagonist altered the decrease in plasma VEGF concentration, fetal retardation, but the C5aRA decreased the number of circulating neutrophils.…”

Section: Carpa In Pregnancymentioning

confidence: 92%

Rodent models of complement activation-related pseudoallergy: Inducers, symptoms, inhibitors and reaction mechanisms

Dézsi

Rosivall

Hamar

et al. 2015

European Journal of Nanomedicine

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Complement activation-related pseudoallergy (CARPA) is a hypersensitivity reaction to intravenous administration of nanoparticle-containing medicines (nanomedicines). This review focuses on CARPA in rodent models: rats, mice, guinea pigs and rabbits. Information on all aspects of hypersensitivity reactions caused by known complement activators (zymosan, cobra venom factor) and different nanomedicines (liposomes, other drug carrier nanocarriers) in these species has been compiled and analyzed, trying to highlight the similarities and differences. What is most common in all species' reactions to i.v. complement activators, liposomes and other nanoparticles is a dose-dependent hemodynamic and cardiopulmonary disturbance manifested in acute, reversible rise or fall of blood pressure and respiratory distress that can lead to shock. Other symptoms include heart rate changes, leukopenia followed by leukocytosis, thrombocytopenia, hemoconcentration due to fluid extravasation (rise of hematocrit) and rise of plasma thromboxane B2. The results of a recent rat study are detailed, which show that rats are 2-3 orders of magnitude less sensitive to liposome-induced CARPA than pigs or hypersensitive humans. It is concluded that CARPA can be studied in rodent models, but they do not necessarily mimic the human reactions in terms of symptom spectrum and sensitivity.

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Differential Effects of Complement Activation Products C3a and C5a on Cardiovascular Function in Hypertensive Pregnant Rats

Cited by 31 publications

References 48 publications

The Complement System and Preeclampsia

The Complement System and Preeclampsia

Role of IgM and angiotensin II Type I receptor autoantibodies in local complement activation in placental ischemia-induced hypertension in the rat

Rodent models of complement activation-related pseudoallergy: Inducers, symptoms, inhibitors and reaction mechanisms

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