Hypertension and Cognitive Dysfunction in a Pregnant Rat Model of PE; a Role for CD4+ T Cells

IF 2.5 3区医学 Q3 IMMUNOLOGY

American Journal of Reproductive Immunology Pub Date : 2024-10-20 DOI:10.1111/aji.13935

Evangeline Deer, Owen Herrock, Kimberly Simmons, Nathan Campbell, Lorena Amaral, Baoying Zheng, Rachael Morris, Kedra Wallace, ELizabeth Hawthorne Cleveland, Sheila Belk, Cameronne Dodd, Babbette LaMarca

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引用次数: 0

Abstract

Objective

Preeclampsia (PE) is associated with hypertension (HTN) during pregnancy and activated CD4+ T cells, inflammatory cytokines, and autoantibodies to the angiotensin II type I receptor (AT1-AA). Having had COVID-19 (CV) during pregnancy is associated with an increased incidence of a PE-like phenotype. Both PE and CV have long-lasting neurological implications and studies show that nonpregnant COVID patients produce AT1-AA. We have shown that CD4+ T cells from PE women cause a PE phenotype in nude athymic rats. In this study, we sought to examine the role of CD4+ T cells from PE with a CV History (Hx) to contribute to a PE phenotype and to determine the importance of CD4+ T cells in cognitive dysfunction during pregnancy.

Methods

At delivery, blood and placentas were collected, and one million placental CD4+ T cells from each PE and each normotensive patient, with (NT) or without (NP) a CV (Hx) during pregnancy, were isolated, purified, and injected i.p. into a gestational day (GD) 12 pregnant nude athymic rat (one patient/rat). At GD19, blood pressure (MAP) and circulating factors were assessed in recipient rats. Cognitive function and memory were assessed using Novel Object Recognition and Barnes Maze tests, respectively. Placental ACE-2 activity and AT1-AA were measured from COVID Hx patients. A one- or two-way ANOVA with Bonferroni's multiple comparisons test was used for statistical analysis.

Results

Blood pressure was increased in patients with PE, with or without COVID, compared to NT patients. There were no significant changes in placental ACE activity in patients with COVID Hx with or without PE. AT1-AA was elevated in PE patients and in both PE and NT COVID Hx compared to control NP. In pregnant recipient rats, MAP increased in CV Hx PE (113 ± 2, n = 8) compared to CV Hx NT (101 ± 5, n = 6). PE and PE CV Hx CD4+ T Cell recipient rats exhibited impaired memory and cognitive dysfunction (p < 0.05), compared to control groups. Recipient rats of PE CV Hx CD4+ T cells had elevated AT1-AA compared to NT CV Hx recipients. Both COVID Hx groups and recipients of PE CD4+ T cells had elevated TNF alpha compared to NP.

Conclusion

Our findings indicate that pregnant patients with a Hx of COVID during pregnancy produce AT1-AA, with or without PE. Recipients of CD4+ T cells from PE with or without a CV Hx during pregnancy cause HTN and elevated AT1-AA. TNF-α is elevated in PE and in CV Hx NT and PE recipients. Interestingly, recipients of T cells from PE patients with or without a Hx of CV had worse cognitive function during pregnancy, compared to recipient rats of NP CD4+ T cells. These data demonstrate the importance of CD4+ T cells in HTN and impaired neurological function during PE in the presence or absence of a prior COVID-19 infection during pregnancy.

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妊娠大鼠 PE 模型中的高血压和认知功能障碍；CD4+ T 细胞的作用

目的子痫前期（PE）与妊娠期高血压（HTN）、活化的 CD4+ T 细胞、炎症细胞因子和血管紧张素 II I 型受体（AT1-AA）自身抗体有关。妊娠期患 COVID-19 （CV）与 PE 类表型的发病率增加有关。PE 和 CV 都会对神经系统产生长期影响，研究表明，非妊娠 COVID 患者会产生 AT1-AA。我们已经证明，来自 PE 妇女的 CD4+ T 细胞会导致裸体无胸腺大鼠出现 PE 表型。在本研究中，我们试图研究有 CV 病史（Hx）的 PE 患者的 CD4+ T 细胞在导致 PE 表型中的作用，并确定 CD4+ T 细胞在妊娠期认知功能障碍中的重要性。方法在分娩时收集血液和胎盘，分离、纯化和注射一百万个来自每个 PE 和每个正常血压患者（妊娠期间有（NT）或无（NP）CV（Hx））的胎盘 CD4+ T 细胞到妊娠日（GD）12 的妊娠裸大鼠体内（每个患者/大鼠一只）。在 GD19 时，对受体大鼠的血压（MAP）和循环因子进行评估。认知功能和记忆分别通过新物体识别和巴恩斯迷宫测试进行评估。对 COVID Hx 患者的胎盘 ACE-2 活性和 AT1-AA 进行了测量。统计分析采用单因素或双因素方差分析，并进行 Bonferroni 多重比较检验。结果与 NT 患者相比，伴有或不伴有 COVID 的 PE 患者血压升高。无论是否患有 COVID，PE 患者的胎盘 ACE 活性均无明显变化。与对照 NP 相比，PE 患者以及 PE 和 NT COVID Hx 患者的 AT1-AA 均升高。在妊娠受体大鼠中，与CV Hx NT（101 ± 5，n = 6）相比，CV Hx PE（113 ± 2，n = 8）的MAP增加。与对照组相比，PE 和 PE CV Hx CD4+ T 细胞受体大鼠表现出记忆力减退和认知功能障碍（p < 0.05）。与NT CV Hx受体相比，PE CV Hx CD4+ T细胞受体大鼠的AT1-AA升高。与 NP 相比，COVID Hx 组和 PE CD4+ T 细胞受体的 TNF α 均升高。结论我们的研究结果表明，无论是否患有 PE，妊娠期患有 COVID 的孕妇都会产生 AT1-AA。无论是否在妊娠期间患过CVID，接受来自PE的CD4+T细胞都会导致高血压和AT1-AA升高。TNF-α在PE、CV Hx NT和PE受体中均升高。有趣的是，与 NP CD4+ T 细胞的受体大鼠相比，有或没有 CV Hx 的 PE 患者的 T 细胞受体在妊娠期间的认知功能更差。这些数据证明了 CD4+ T 细胞在高血压和 PE 期间神经功能受损中的重要性，无论是否在妊娠期间感染过 COVID-19。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

American Journal of Reproductive Immunology 医学-免疫学

CiteScore

6.20

自引率

5.60%

发文量

314

审稿时长

2 months

期刊介绍： The American Journal of Reproductive Immunology is an international journal devoted to the presentation of current information in all areas relating to Reproductive Immunology. The journal is directed toward both the basic scientist and the clinician, covering the whole process of reproduction as affected by immunological processes. The journal covers a variety of subspecialty topics, including fertility immunology, pregnancy immunology, immunogenetics, mucosal immunology, immunocontraception, endometriosis, abortion, tumor immunology of the reproductive tract, autoantibodies, infectious disease of the reproductive tract, and technical news.