Th17 cell-linked mechanisms mediate vascular dysfunction induced by testosterone in a mouse model of gender-affirming hormone therapy

Sex hormone-induced cardiovascular events are important undesirable effects in transgender people under GAHT. Studies addressing the cardiovascular impact of GAHT will certainly contribute to improve healthcare services offered to this population. Our study showing that vascular dysfunction, via Th1...

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Published in:American journal of physiology. Heart and circulatory physiology 2022-08, Vol.323 (2), p.H322-H335
Main Authors: Santos, Jeimison D., Oliveira-Neto, José T., Barros, Paula R., Damasceno, Luis E. A., Lautherbach, Natalia, Assis, Ana P., Silva, Carlos A. A., Sorgi, Carlos A., Faccioli, Lucia H., Kettelhut, Isis C., Salgado, Hélio C., Carneiro, Fernando S., Alves-Filho, José C., Tostes, Rita C.
Format: Article
Language:English
Subjects:
Adoptive transfer
Animal models
Blood pressure
Body fat
Body mass
Body mass index
Body size
Cardiovascular diseases
Cardiovascular system
CD4 antigen
Cell activation
Data points
Endocrine therapy
Endothelium
Females
Gender
Gender-affirming care
Health risks
Helper cells
Hormone replacement therapy
Hormones
Interleukin 17
Lean body mass
Lymphocytes
Lymphocytes B
Lymphocytes T
Males
Ovariectomy
RAG1 protein
Rodents
Sex hormones
Testosterone
Therapy
Vasodilation
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Summary:Sex hormone-induced cardiovascular events are important undesirable effects in transgender people under GAHT. Studies addressing the cardiovascular impact of GAHT will certainly contribute to improve healthcare services offered to this population. Our study showing that vascular dysfunction, via Th17 cell-related mechanisms, precedes increased blood pressure induced by testosterone in a GAHT mouse model, reveals potential mechanisms involved in GAHT-related cardiovascular events and may provide new markers/targets for clinical practices in transmasculine people. Clinical data point to adverse cardiovascular events elicited by testosterone replacement therapy. Testosterone is the main hormone used in gender-affirming hormone therapy (GAHT) by transmasculine people. However, the cardiovascular impact of testosterone in experimental models of GAHT remains unknown. Sex hormones modulate T-cell activation, and immune mechanisms contribute to cardiovascular risk. The present study evaluated whether testosterone negatively impacts female cardiovascular function by enhancing Th17 cell-linked effector mechanisms. Female (8 wk old) C57BL/6J mice received testosterone (48 mg/kg/wk) for 8 wk. Male mice were used for phenotypical comparisons. The hormone treatment in female mice increased circulating testosterone to levels observed in male mice. Testosterone increased lean body mass and body mass index, and decreased perigonadal fat mass, mimicking clinical findings. After 8 wk, testosterone decreased endothelium-dependent vasodilation and increased peripheral Th17 cells. After 24 wk, testosterone increased blood pressure in female mice. Ovariectomy did not intensify phenotypical or cardiovascular effects by testosterone. Female mice lacking T and B cells [Rag1 knockout ( −/− )], as well as female mice lacking IL-17 receptor (IL-17Ra −/− ), did not exhibit vascular dysfunction induced by testosterone. Testosterone impaired endothelium-dependent vasodilation in female mice lacking γδ T cells, similarly to the observed in wild-type female mice. Adoptive transfer of CD4 + T cells restored testosterone-induced vascular dysfunction in Rag1 −/− female mice. Together, these data suggest that CD4 + T cells, most likely Th17 cells, are central to vascular dysfunction induced by testosterone in female mice, indicating that changes in immune-cell balance are important in the GAHT in transmasculine people. NEW & NOTEWORTHY Sex hormone-induced cardiovascular events are important un
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00182.2022