Menopause and foxp3 treg cell depletion eliminate female protection against t cell-mediated angiotensin ii hypertension

Dennis P. Pollow, Joshua A. Uhlorn, Megan A. Sylvester, Melissa J. Romero-Aleshire, Jennifer L. Uhrlaub, Merry L. Lindsey, Janko Nikolich-Zugich, Heddwen L Brooks

Research output: Contribution to journalArticle

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Abstract

Although it is known that the prevalence and severity of hypertension increases in women after menopause, the contribution of T cells to this process has not been explored. Although the immune system is both necessary and required for the development of angiotensin II (ANG II) hypertension in men, we have demonstrated that premenopausal women are protected from T cell-mediated hypertension. The goal of the current study was to test the hypotheses that 1) female protection against T cell-mediated ANG II hypertension is eliminated following progression into menopause and 2) T regulatory cells (Tregs) provide premenopausal protection against ANG II-induced hypertension. Menopause was induced in Rag-1+/+ mice (via 4-vinylcyclohexene diepoxide), and all mice received a 14-day ANG II infusion. Donor CD3 T cells were adoptively transferred 3 wk before ANG II infusion. In the absence of T cells, systolic blood pressure responses to ANG II were similar to those seen in premenopausal mice (Δ12 mmHg). After adoptive transfer of T cells, ANG II significantly increased systolic blood pressure in postmenopausal females (Δ28 mmHg). A significant increase in F4/80 positive renal macrophages, an increase in renal inflammatory gene expression, along with a reduction in renal expression of mannose receptor C-type 1, a marker for M2 macrophages, accompanied the increase in systolic blood pressure (SBP). Flow cytometric analysis identified that Tregs were significantly decreased in the spleen and kidneys of Rag-1+/+ menopausal mice versus premenopausal females, following ANG II infusion. In a validation study, an anti-CD25 antibody was used to deplete Tregs in premenopausal mice, which induced a significant increase in SBP. These results demonstrate that premenopausal protection against T cell-mediated ANG II hypertension is eliminated once females enter menopause, suggesting that a change in hormonal status upregulates macrophage-induced proinflammatory and T cell-dependent responses. Furthermore, we are the first to report that the presence of Tregs are required to suppress ANG II hypertension in premenopausal females.

Original languageEnglish (US)
Pages (from-to)H415-H423
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume317
Issue number2
DOIs
StatePublished - Aug 1 2019

Fingerprint

Angiotensins
Regulatory T-Lymphocytes
Menopause
Angiotensin II
Hypertension
Blood Pressure
T-Lymphocytes
Kidney
Macrophages
Adoptive Transfer
Validation Studies
Anti-Idiotypic Antibodies
Immune System
Up-Regulation
Spleen
Tissue Donors
Gene Expression

Keywords

  • Inflammation
  • Kidney
  • Macrophage
  • Ovarian failure
  • T cells
  • VCD

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Menopause and foxp3 treg cell depletion eliminate female protection against t cell-mediated angiotensin ii hypertension. / Pollow, Dennis P.; Uhlorn, Joshua A.; Sylvester, Megan A.; Romero-Aleshire, Melissa J.; Uhrlaub, Jennifer L.; Lindsey, Merry L.; Nikolich-Zugich, Janko; Brooks, Heddwen L.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 317, No. 2, 01.08.2019, p. H415-H423.

Research output: Contribution to journalArticle

Pollow, Dennis P. ; Uhlorn, Joshua A. ; Sylvester, Megan A. ; Romero-Aleshire, Melissa J. ; Uhrlaub, Jennifer L. ; Lindsey, Merry L. ; Nikolich-Zugich, Janko ; Brooks, Heddwen L. / Menopause and foxp3 treg cell depletion eliminate female protection against t cell-mediated angiotensin ii hypertension. In: American Journal of Physiology - Heart and Circulatory Physiology. 2019 ; Vol. 317, No. 2. pp. H415-H423.
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