Author ORCID Identifier
Date Available
12-15-2024
Year of Publication
2023
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Medicine
Department/School/Program
Pharmacology and Nutritional Sciences
First Advisor
Dr. Zhenheng Guo
Abstract
Aortic aneurysms, a permanent enlargement in the aorta, is a devastating disease with a high mortality rate after rupture. Aortic aneurysms exhibit strong sex dimorphisms: men are at higher risk than women while women experience worse outcomes if diagnosed. Currently, the only intervention is by open surgery or endovascular repair, and no drugs are approved for blunting the disease progression. This highlights the needs for mechanistic studies for sex-specific therapeutic targets.
Our lab established the mouse model in which mineralocorticoid receptor (MR) agonist aldosterone induces aortic aneurysms in the presence of high salt in male mice age-dependently, mimicking the aging pattern in clinical observation. However, whether the Aldo-salt model exhibits sex dimorphisms like humans is unknown.
The current study first demonstrated a strong sex-dependent phenotype in Aldo-salt-induced aortic aneurysms in 10-month-old male and female mice. Next, we performed gonadectomy on male and female mice to study the effects of male and female sex hormones on Aldo-salt-induced aortic aneurysms respectively, and we identified two distinct hormone-specific mechanisms.
In male mice, we showed that orchiectomy provided strong protection against aneurysm development mediated by the androgen-androgen receptor axis. Next, by unbiased RNA-seq, we revealed that androgen deprivation is associated with upregulated T cell receptor signaling and PD-1 signaling pathway. Moreover, we indicated that increased PD-1+ T cells in the aorta were associated with splenectomy-attenuated aortic aneurysms in response to Aldo-salt. To gain mechanistic insights into the regulation between androgen and PD-1, we performed a series of experiments and demonstrated that PD-1 was upregulated in the spleen of orchiectomized mice than that of sham mice at both protein and mRNA levels. Moreover, we showed that AR can bind to the PD-1 promoter and exert suppression on PD-1 transcription. The PD-1 changes in the spleen were also mirrored in the blood and partially in the aorta, suggesting possible effects on vascular inflammation via circulating T cells. Most importantly, by injecting an anti-PD-1 antibody and adoptive transfer of PD-1-/- T cells, we successfully reinstated the aortic aneurysms formation in orchiectomized mice. Furthermore, using Ang II and HFD in intact male mice, we showed that PD-1-/- exacerbated the aortic aneurysms compared to wildtype mice. Collectively, we demonstrated the important role of PD-1 in the pathogenesis of aortic aneurysms, and its transcription was suppressed by the androgen receptor.
In female mice, we found that ovariectomy abolished the female protection against Aldo-salt-induced aortic aneurysms in 11-12-month-old mice. Such effects were not observed in 3-month-old mice, suggesting the age-dependent fashion as in humans. Next, we used multiple approaches to study the underlying mechanisms involved both aging and estrogen, and we found that MR showed a strong aging pattern, and it was upregulated, activated, and translocated into the nucleus upon aldosterone only with the absence of estrogen. Interestingly, such changes were more sensitive in vascular endothelial cells. Moreover, specific deletion of MR from endothelium mitigated the Aldo-salt-induced aortic aneurysms in aged ovariectomized mice, possibly via the downstream cellular senescence.
In summary, our findings demonstrate the sex dimorphisms in Aldo-salt-induced aortic aneurysms. The promoting role of androgen and the protective role of estrogen are by two distinct mechanisms: 1) warranting the caution for cancer patients on immune checkpoint inhibitors of the potential risk of developing aortic aneurysms; and 2) giving rise to MR as a potential therapeutic target specifically for aged menopausal women.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2023/470
Funding Information
This study was supported by the National Institutes of Health Grants, HL125228 in 2015, HL141103 in 2019, HL142973 in 2018, and HL164398 in 2022
Recommended Citation
Mu, Xufang, "SEX DIMORPHISMS OF ALDOSTERONE AND HIGH SALT INDUCED AORTIC ANEURYSMS IN MICE" (2023). Theses and Dissertations--Pharmacology and Nutritional Sciences. 54.
https://uknowledge.uky.edu/pharmacol_etds/54
