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Angiotensin II Increases Oxidative Stress and Inflammation in Female, But Not Male, Endothelial Cells

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Abstract

Introduction

Women are at elevated risk for certain cardiovascular diseases, including pulmonary arterial hypertension, Alzheimer’s disease, and vascular complications of diabetes. Angiotensin II (AngII), a circulating stress hormone, is elevated in cardiovascular disease; however, our knowledge of sex differences in the vascular effects of AngII are limited. We therefore analyzed sex differences in human endothelial cell response to AngII treatment.

Methods

Male and female endothelial cells were treated with AngII for 24 h and analyzed by RNA sequencing. We then used endothelial and mesenchymal markers, inflammation assays, and oxidative stress indicators to measure female and male endothelial cell functional changes in response to AngII.

Results

Our data show that female and male endothelial cells are transcriptomically distinct. Female endothelial cells treated with AngII had widespread gene expression changes related to inflammatory and oxidative stress pathways, while male endothelial cells had few gene expression changes. While both female and male endothelial cells maintained their endothelial phenotype with AngII treatment, female endothelial cells showed increased release of the inflammatory cytokine interleukin-6 and increased white blood cell adhesion following AngII treatment concurrent with a second inflammatory cytokine. Additionally, female endothelial cells had elevated reactive oxygen species production compared to male endothelial cells after AngII treatment, which may be partially due to nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX2) escape from X-chromosome inactivation.

Conclusions

These data suggest that endothelial cells have sexually dimorphic responses to AngII, which could contribute to increased prevalence of some cardiovascular diseases in women.

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Data Availability

All RNA sequencing data is publicly available under GSE211978.

Abbreviations

SORCS2:

Sortilin related VPS10 domain containing receptor 2

CCR7:

Chemokine (C–C motif) receptor 7

TPM3P7:

Tropomycin 3 psuedogene 7

SIM1:

Single-minded homolog 1

IL-6:

Interleukin-6

TGF-β2:

Transforming growth factor beta 2

LSS:

Lanosterol synthase

DHX16:

DEAH-box helicase 16

WASH8P:

WAS protein family homolog 8, pseudogene

CDNF:

Cerebral dopamine neurotrophic factor

GTF2H2:

General transcription factor IIH subunit II

RRN3:

RNA polymerase I transcription factor

GBA:

Glucosylceramidase beta 1

NDUFC2:

NADH:Ubiquinone oxidoreductase subunit C2

NDUFA1:

NADH:Ubiquinone oxidoreductase subunit A1

UQCR10:

Ubiquinol-cytochrome C reductase, complex III, subunit X

UQCRQ:

Ubiquinol-cytochrome C reductase, complex III, subunit VII

COX6A1:

Cytochrome C oxidase subunit 6A1

COX7C:

Cytochrome C oxidase subunit 7C

COX17:

Cytochrome C oxidase copper chaperone

ATP5F1E:

ATP synthase F1 subunit epsilon

ATP5ME:

ATP synthase membrane subunit E

CYBB:

Cytochrome B-245 beta chain

NOX2:

NADPH oxidase 2

αSMA:

Alpha smooth muscle actin

TNFα:

Tumor necrosis factor alpha

ARID5A:

AT-Rich interaction domain 5A

ZC3H12A:

Reagenase-1

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Funding

The authors gratefully acknowledge funding support from the National Institutes of Health (Grant Nos. R21EB028466 and R01HL140239-01) to AMC, the National Science Foundation (Grant Nos. CMMI 1916814 and CBET 1916997) to AMC, the Brain and Behavior Initiative at the University of Maryland through the BBI Seed Grant Program to AMC, NIMHD 5U54MD013376 subproject 8281 to DFD, the National Science Foundation Graduate Research Fellowship Program (Grant No. DGE 1840340) to CMW, NSF REU 1757745 to MNH, the University of Maryland ASPIRE program to SMZ, the University of Maryland Presidential Postdoctoral Fellowship to GSS, and the American Heart Association Postdoctoral Fellowship 916512 to GSS.

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Authors and Affiliations

  1. Fischell Department of Bioengineering, University of Maryland, 8278 Paint Branch Dr., College Park, MD, 20742, USA

    Callie M. Weber, Sophia M. Zic, Gurneet S. Sangha & Alisa Morss Clyne

  2. Department of Biology, Morgan State University, Baltimore, MD, 21251, USA

    Mikayla N. Harris, Nicole S. Arnold & Douglas F. Dluzen

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Contributions

CMW and AMC conceived and designed the research. CMW, MNH, SMZ, and GS carried out the experiments. CMW, MNH, SMZ, NA, and DD analyzed data. CMW, MNH, SMZ, DFD, and AMC interpreted results of experiments. CMW and AMC prepared figures and drafted manuscript. CMW, MNH, SMZ, NA, DFD, and AMC edited, revised, and approved the final version of the manuscript.

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Correspondence to Alisa Morss Clyne.

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Callie M. Weber, Mikayla N. Harris, Sophia M. Zic, Gurneet S. Sangha, Nicole S. Arnold, Douglas F. Dluzen, and Alisa Morss Clyne do not have any conflicts of interest, financial or otherwise, to declare.

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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients being included in the study.

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Weber, C.M., Harris, M.N., Zic, S.M. et al. Angiotensin II Increases Oxidative Stress and Inflammation in Female, But Not Male, Endothelial Cells. Cel. Mol. Bioeng. 16, 127–141 (2023). https://doi.org/10.1007/s12195-023-00762-2

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