Sex differences in cardiac anti-inflammatory cytokines in adult intrauterine growth restricted rodents

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Background: Approximately 5-10% of U.S. pregnancies are affected by intrauterine growth restriction (IUGR), which is often due to placental ischemia. Adults who were exposed to IUGR have a higher risk of developing cardiovascular diseases (CVD), in which there are sex differences where IUGR males show greater risk of CVD morbidities. One plausible mechanism is cardiac inflammation. Multiple studies have shown that IUGR offspring have increased pro-inflammatory cytokines, such as TNF-α, IL-6, and IFN-γ, that are present in the circulation and heart. However, few studies have explored anti-inflammatory cytokines in the hearts of adult IUGR offspring. Thus, the objective of this study is to investigate alterations in blood pressure (BP) and cardiac IL-4 and IL-10 in adult male and female IUGR offspring. We hypothesize that IUGR males will have higher BP accompanied by decreased cardiac IL-4 and IL-10, while these cytokines will remain unchanged in IUGR females. Methods: Pregnant Sprague Dawley rats were randomly divided into two groups: normal and placental ischemic (PI) dams. On gestational day 14, the reduced uterine perfusion pressure surgery was performed to induce PI. Our PI dams generated IUGR offspring while the normal pregnant dams generated control (CON) offspring. All pups were born naturally and weaned for 3 weeks. At 16-18 weeks (adulthood), the offsprings’ BP was recorded via a carotid catheterization. Hearts were then collected and homogenized to measure IL-4 and IL-10 levels via ELISAs. Results: BP increased in IUGR vs CON males (136±2 vs. 120±7mmHg, p<0.05), whereas BP in IUGR vs CON females was unchanged. Cardiac IL-4 was elevated in females compared to males (p<0.05) and in IUGR compared to CON (p=0.0002). IL-4 exhibited a greater increase of ~63% in IUGR vs CON females (306.6±17.1 vs. 188.0±22.6pg/mg, p< 0.05) and 45% increase in IUGR vs CON males (216.8±19.2 vs. 149.5±23.4pg/mg, p< 0.05). Furthermore, IUGR females showed a 41% increase in IL-4 levels compared to IUGR males (306.6±17.1 vs. 216.8±19.2pg/mg, p< 0.05). There were no changes in cardiac IL-10 in all groups. Conclusion: IUGR males displayed elevated BP compared to CON males, while females displayed no differences. Surprisingly, IL-4 concentrations were increased with IUGR status in both sexes, with a greater increase in IUGR vs CON females. Moreover, IL-4 was elevated in females vs males. This increase in IL-4 in females may be a protective mechanism to prevent future cardiac dysfunction. Previous studies have shown IL-4 aids in tissue repair, but chronically elevated IL-4 is linked to adverse cardiac remodeling. More studies are needed to determine the sexually dimorphic role of cardiac IL-4 in this IUGR model. Cardiac IL-10 was unchanged in all groups, suggesting that its role in BP regulation and CVD is not as critical as IL-4. This study is clinically relevant because it highlights the sex differences and the role of cardiac anti-inflammatory cytokines to increase the risk of CVD in adult IUGR offspring. 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.

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