Related Experiment Video
Updated: Jun 26, 2026
Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice
Published on: September 28, 2015
Androgen aggravates aortic aneurysms via suppression of PD-1 in mice
Xufang Mu1, Shu Liu2, Zhuoran Wang1
1Departments of Pharmacology and Nutritional Sciences.
Insights
Androgens worsen aortic aneurysms (AAs) by suppressing programmed cell death protein 1 (PD-1) in T cells. This discovery reveals a key mechanism in male cardiovascular disease and suggests cancer patients on immunotherapy may need AA screening.
Area of Science:
- Cardiovascular Biology
- Immunology
- Endocrinology
Background:
- Aortic aneurysms (AAs) exhibit significant sexual dimorphism, with higher prevalence and mortality in men.
- The precise mechanisms by which androgens contribute to AA development remain largely undefined.
Purpose of the Study:
- To elucidate the role of androgens and androgen receptors (ARs) in the sex-specific development of aortic aneurysms.
- To identify molecular pathways linking androgen signaling to AA pathogenesis.
Main Methods:
- Utilized a mouse model of aldosterone and high salt (Aldo-salt) induced aortic aneurysms.
- Investigated the expression and function of programmed cell death protein 1 (PD-1) in the context of androgen signaling and AA.
- Employed orchiectomy, anti-PD-1 antibody administration, and adoptive T cell transfer to assess the role of PD-1.
Main Results:
- Male mice, but not female mice, developed AAs upon Aldo-salt exposure, dependent on androgens and ARs.
- Programmed cell death protein 1 (PD-1) was identified as a critical mediator linking androgens to AAs.
- Modulation of PD-1 levels (via antibody or genetic deletion) significantly impacted AA development in various experimental settings.
- AR was found to directly bind the PD-1 promoter, suppressing its expression in splenic T cells.
Conclusions:
- Androgen signaling exacerbates aortic aneurysms by suppressing PD-1 expression in T cells, revealing a novel mechanism for sexual dimorphism in vascular disease.
- Targeting PD-1 or understanding androgen-mediated immune suppression may offer therapeutic strategies for AAs.
- Suggests potential benefit of AA screening in cancer patients undergoing immune checkpoint inhibitor therapy.
Abstract:
Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms (AAs), a devastating vascular disease with a higher prevalence and fatality rate in men than in women. However, the mechanism by which androgen mediates AAs is largely unknown. Here, we found that male, not female, mice developed AAs when exposed to aldosterone and high salt (Aldo-salt). We revealed that androgen and androgen receptors (ARs) were crucial for this sexually dimorphic response to Aldo-salt. We identified programmed cell death protein 1 (PD-1), an immune checkpoint, as a key link between androgen and AAs. Furthermore, we demonstrated that administration of anti-PD-1 Ab and adoptive PD-1-deficient T cell transfer reinstated Aldo-salt-induced AAs in orchiectomized mice and that genetic deletion of PD-1 exacerbated AAs induced by a high-fat diet and angiotensin II (Ang II) in nonorchiectomized mice. Mechanistically, we discovered that the AR bound to the PD-1 promoter to suppress the expression of PD-1 in the spleen. Thus, our study unveils a mechanism by which androgen aggravates AAs by suppressing PD-1 expression in T cells. Moreover, our study suggests that some patients with cancer might benefit from screenings for AAs during immune checkpoint therapy.
