Immune training by angiotensin II exhibits sex-specific responses

Background: Chronic inflammation is a major driver of atherosclerotic cardiovascular disease (ASCVD). Indeed, immunomodulatory therapies have been shown to reduce cardiac events beyond conventional risk-modifying therapy. While hypertension (HTN) is the primary modifiable risk factor for ASCVD, treatment with blood pressure-lowering therapy does not fully mitigate risk of future cardiac events. While this residual risk is believed to be due to chronic inflammation, the mechanisms by which HTN drives sustained inflammation even after treatment remain unclear. Furthermore, while female sex is protective against ASCVD, the role of sex in modulating HTN-associated risk is poorly understood. Our lab recently showed that transient angiotensin II (Ang II) exposure in male mice causes persistent immune changes by inducing a form of innate immune memory known as trained immunity. Furthermore, Ang II-induced immune training leads to worsened atherosclerosis in male atheroprone mice. Hypothesis: Female innate immune cells will exhibit a blunted trained immune response to Ang II, thus mitigating ASCVD risk conferred by Ang II-driven trained immunity. Methods: Male and female C57BL/6 mice were implanted with osmotic minipumps (Alzet Corp) to infuse vehicle (Veh) or Ang II (Ang) (490 ng/kg/min) over 2 weeks. At the end of two weeks, blood pressure was measured by tail-cuff plethysmography and mice were euthanized. Bone marrow was harvested and transplanted into sex-matched irradiated LDLR KO mice. Recipient groups are denoted by donor sex/treatment followed by recipient sex. For example, male Veh → male LDLR KO: VM-LDLR-M. After recovery, recipient mice were fed a Western diet (WD) for 10 weeks. Results: Two weeks of Ang II infusion increased systolic blood pressure in male and female mice relative to Veh controls (in mmHg, 160.99±6.03 vs 120.29±6.67, p< 0.0001 and 158.89±13.27 vs 118.56±8.28, p< 0.0001, respectively). Male Ang-infused mice had elevated total white blood cell (WBC) counts (in K/µL, 7.69±2.68 vs 4.34±1.16, p=0.002) and monocytes (4.31%±1.77 vs 2.25%±0.83, p=0.0017) relative to male Veh mice. However, there were no significant differences in WBCs (in K/µL, 3.84±1.07 vs 5.04±1.12, p=0.2384) or percent monocytes (4.56%±0.95 vs 4.56%±0.86, p=0.9964) between female Ang- vs Veh-infused mice. Male recipients of marrow from male Ang donors (AM-LDLR-M) exhibited a significant increase in circulating monocytes (3.67%±1.43 vs 2.04%±0.63, p=0.0248) and a skewing towards Ly6C-high pro-inflammatory monocytes compared to male Veh donors (VM-LDLR-M). Furthermore, atherosclerotic lesions in the AM-LDLR-M group were significantly larger than the VM-LDLR-M group (in µm2, 257052.82±43477.15 vs 162844.06±68130.12, p=0.003). In female recipients, there was no difference in lesion area between AF-LDLR-F and VF-LDLR-F groups (in µm2, 132320.65±18312.77 vs 185087.34±69566.00, p=0.2258). The AF-LDLR-F group also showed no significant difference in circulating monocyte percentages compared to the VF-LDLR-F group (5.08%±2.18 vs 4.4%±0.80, p=0.4847). Conclusions: In male mice, Ang II induces trained immunity, creating a transferrable immune phenotype that accelerates atherogenesis in male bone marrow recipients. In contrast, female mice exhibit a blunted innate immune response to Ang II, and female recipients exhibit no differences in atherosclerosis severity when receiving marrow from female hyper- vs normotensive donors. These data suggest that female mice are resistant to Ang II-induced trained immunity, highlighting a previously undescribed immune-mediated mechanism underlying sex differences in ASCVD risk. R01 HL174961. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.