Angiotensin II type 1 receptor autoantibody blockade improves cerebral blood flow autoregulation and hypertension in a preclinical model of preeclampsia

Duncan, Jeremy W.; Azubuike, Daniel; Booz, George W.; Fisher, Brandon; Fan, Fan; Ibrahim, Tarek; LaMarca, Babbette; Cunningham, Mark

doi:10.1080/10641955.2020.1833215

Cited by 10 publications

(9 citation statements)

References 57 publications

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“…Patients with HDP exhibited greater vascular reactivity to AT II ( 238 ), and serum from pregnant patients with HDP but not those with essential hypertension contained AT1 autoantibodies (AAs) that could stimulate AT II receptor 1 ( 239 ). AT1-autoantibodies that were isolated from women with HDP reproduce key features of HDP in mice ( 240 ), and their pharmacological blockade normalized maternal blood pressure during pregnancy ( 241 ). Exposure to LPS during pregnancy gave rise to features that are relevant to HDP in rats offspring, which was prevented by treatment with the AT II receptor inhibitor losartan ( 242 ).…”

Section: Hypertensive Disorders Of Pregnancymentioning

confidence: 99%

Influence of Prenatal Drug Exposure, Maternal Inflammation, and Parental Aging on the Development of Autism Spectrum Disorder

et al. 2022

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Autism spectrum disorder (ASD) affects reciprocal social interaction and produces abnormal repetitive, restrictive behaviors and interests. The diverse causes of ASD are divided into genetic alterations and environmental risks. The prevalence of ASD has been rising for several decades, which might be related to environmental risks as it is difficult to consider that the prevalence of genetic disorders related to ASD would increase suddenly. The latter includes (1) exposure to medications, such as valproic acid (VPA) and selective serotonin reuptake inhibitors (SSRIs) (2), maternal complications during pregnancy, including infection and hypertensive disorders of pregnancy, and (3) high parental age. Epidemiological studies have indicated a pathogenetic role of prenatal exposure to VPA and maternal inflammation in the development of ASD. VPA is considered to exert its deleterious effects on the fetal brain through several distinct mechanisms, such as alterations of γ-aminobutyric acid signaling, the inhibition of histone deacetylase, the disruption of folic acid metabolism, and the activation of mammalian target of rapamycin. Maternal inflammation that is caused by different stimuli converges on a higher load of proinflammatory cytokines in the fetal brain. Rodent models of maternal exposure to SSRIs generate ASD-like behavior in offspring, but clinical correlations with these preclinical findings are inconclusive. Hypertensive disorders of pregnancy and advanced parental age increase the risk of ASD in humans, but the mechanisms have been poorly investigated in animal models. Evidence of the mechanisms by which environmental factors are related to ASD is discussed, which may contribute to the development of preventive and therapeutic interventions for ASD.

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Section: Hypertensive Disorders Of Pregnancymentioning

confidence: 99%

Influence of Prenatal Drug Exposure, Maternal Inflammation, and Parental Aging on the Development of Autism Spectrum Disorder

et al. 2022

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“…This evidence has been summarized in recent reviews, 19,45,88 and in Figure 2. Although little information is available about the potential circulating mediators, several candidates have been studied, including VEGF (vascular endothelial growth factor), 100,112 TNF-α, 101,113 oxLDL (oxidized low-density lipoprotein), 114,115 AT1-AA (angiotensin II type I receptor), 116 and placental extracellular vesicles. 117,118 Over the following sections, these underlying factors are discussed.…”

Section: Proposed Mechanisms Of Endothelial Dysfunction At the Matern...mentioning

confidence: 99%

“…141 A later study showed that the AT1-AA antagonist n7AAc apart from attenuating the negative effects on cerebral blood flow autoregulation, decreased BBB permeability, cerebral edema, and oxidative stress in RUPP dams. 116…”

Section: Oxldl and At1-aamentioning

confidence: 99%

Brain Vascular Dysfunction in Mothers and Their Children Exposed to Preeclampsia

et al. 2023

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Preeclampsia is a maternal syndrome characterized by the new onset of hypertension and proteinuria after 20 weeks of gestation associated with multisystemic complications, including brain alterations. Indeed, brain complications associated with preeclampsia are the leading direct causes of fetal and maternal morbidity and mortality, especially in low- and middle-income countries. In addition to the well-recognized long-term adverse cardiovascular effects of preeclampsia, women who have had preeclampsia have higher risk of stroke, dementia, intracerebral white matter lesions, epilepsy, and perhaps also cognitive decline postpartum. Furthermore, increasing evidence has also associated preeclampsia with similar cognitive and cerebral disorders in the offspring. However, the mechanistic links between these associations remain unresolved. This article summarizes the current knowledge about the cerebrovascular complications elicited by preeclampsia and the potential pathophysiological mechanisms involved, emphasizing the impaired brain vascular function in the mother and their offspring.

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“…17,18 Moreover, inhibiting AT1-AA with a specific peptide has shown promise in improving various preeclampsia characteristics in this model but has never been tested in response to IL-17. [16][17][18][19][20][21][22][23] We have previously demonstrated that the adoptive transfer of CD4+ T helper cells from the reduced uterine perfusion pressure (RUPP) model of PE into normal pregnant (NP) rats resulted in a PE phenotype. 11,23,24 A study by Zenclussen et al also demonstrated that the adoptive transfer of splenocytes, cultured in TH1-promoting media, caused PE symptoms in normal pregnant mice.…”

Section: Introductionmentioning

confidence: 99%

“…This further lead to Natural Killer (NK) cell activation, release of soluble fms‐like tyrosine kinase‐1 (sFlt‐1), and mitochondrial dysfunction which culminates in hypertension in pregnant rats 17,18 . Moreover, inhibiting AT1‐AA with a specific peptide has shown promise in improving various preeclampsia characteristics in this model but has never been tested in response to IL‐17 16–23 …”

Section: Introductionmentioning

confidence: 99%

The role of T cell stimulated agonistic autoantibodies to the angiotensin II type I receptor (AT1‐AA) in mediating multiorgan dysfunction in IL‐17 induced hypertension during pregnancy

Hogg,

Campbell,

Deer

et al. 2024

American J Rep Immunol

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ProblemPreeclampsia (PE), new‐onset hypertension during pregnancy accompanied by organ dysfunction, is associated with chronic inflammation including elevated IL‐17, CD4+ T cells, B cells and natural killer (NK) cells. IL‐17 can serve as a signal for either the adaptive or innate immune activation. We have previously shown that IL‐17 contributes to increased blood pressure in association with elevated TH17 cells, NK cells and B cells secreting angiotensin II type 1 receptor agonistic autoantibodies (AT1‐AA) during pregnancy. Moreover, we have shown an important role for CD4+T cells and AT1‐AA in multiorgan dysfunction as measured by mitochondrial oxidative stress (mt ROS). However, we do not know the role of adaptive immune cells such as T cells or B cells secreting AT1‐AA in mediating the PE phenotype in response to elevated IL‐17.Method of studyIn order to answer this question, we infused IL‐17 (150 pg/day i.p.) into either Sprague Dawley (SD) or athymic nude rats via mini‐osmotic pump from gestational day (GD) 14–19 of pregnancy. On GD 19, blood pressure was determined and NK cells, mtROS and respiration and AT1‐AA production from B cells were measured.ResultsInfusion of IL‐17 increased blood pressure in the presence or absence of T cells. Mean arterial pressure (MAP) increased with IL‐17 from 98 ± 2 mm Hg (n = 12) to 114 ± 2 (n = 12) in SD rats and from 99 ± 4 mm Hg (n = 7) versus 115 ± 2 mm Hg (n = 7) in athymic nude rats. Similar trends were seen in NK cells and placental mt ROS. Knowing that IL‐17 stimulates AT1‐AA in SD pregnant rats, we included a group of SD and athymic nude pregnant rats infused with IL‐17 and the AT1‐AA inhibitor peptide (‘n7AAc’). The inhibitor attenuated blood pressure (104.9 ± 3.2, p = .0001) and normalized NK cells and mt function in SD pregnant rats. Importantly, the AT1‐AA was not produced in pregnant nude IL‐17 treated rats, nor did ‘n7AAc’ effect MAP, in nude athymic rats.ConclusionThese findings suggest two conclusions; one is that IL‐17 causes hypertension and multiorgan dysfunction in the absence of T cells and AT1‐AA, possibly through its activation of innate cells and secondly, in the presence of T cells, blockade of the AT1‐AA attenuates the effect of IL‐17. This study indicates the critical effects of elevated IL‐17 during pregnancy and suggest treatment modalities to consider for PE women.

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Angiotensin II type 1 receptor autoantibody blockade improves cerebral blood flow autoregulation and hypertension in a preclinical model of preeclampsia

Cited by 10 publications

References 57 publications

Influence of Prenatal Drug Exposure, Maternal Inflammation, and Parental Aging on the Development of Autism Spectrum Disorder

Influence of Prenatal Drug Exposure, Maternal Inflammation, and Parental Aging on the Development of Autism Spectrum Disorder

Brain Vascular Dysfunction in Mothers and Their Children Exposed to Preeclampsia

The role of T cell stimulated agonistic autoantibodies to the angiotensin II type I receptor (AT1‐AA) in mediating multiorgan dysfunction in IL‐17 induced hypertension during pregnancy

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