BACKGROUND: Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common endocrine disease in women of reproductive age, is associated with an increased prevalence and extent of coronary artery disease. However, the mechanism through which PCOS affects cardiac health in women remains unclear. METHODS: Prenatal anti-Müllerian hormone treatment or peripubertal letrozole infusion was used to establish mouse models of PCOS. RNA sequencing was performed to determine global transcriptomic changes in the hearts of PCOS mice. Flow cytometry and immunofluorescence staining were performed to detect myocardial macrophage accumulation in multiple PCOS models. Parabiosis models, cell-tracking experiments, and in vivo gene silencing approaches were used to explore the mechanisms underlying increased macrophage infiltration in PCOS mouse hearts. Permanent coronary ligation was performed to establish myocardial infarction (MI). Histologic analysis and small-animal imaging modalities (eg, magnetic resonance imaging and echocardiography) were performed to evaluate the effects of PCOS on injury after MI. Women with PCOS and control participants (n=200) were recruited to confirm findings observed in animal models. RESULTS: Transcriptomic profiling and immunostaining revealed that hearts from PCOS mice were characterized by increased macrophage accumulation. Parabiosis studies revealed that monocyte-derived macrophages were significantly increased in the hearts of PCOS mice because of enhanced circulating Ly6C ⁺ monocyte supply. Compared with control mice, PCOS mice showed a significant increase in splenic Ly6C ⁺ monocyte output, associated with elevated hematopoietic progenitors in the spleen and sympathetic tone. Plasma norepinephrine (a sympathetic neurotransmitter) levels and spleen size were consistently increased in women with PCOS when compared with those in control participants, and norepinephrine levels were significantly correlated with circulating CD14 ⁺⁺ CD16 ⁻ monocyte counts. Compared with animals without PCOS, PCOS animals showed significantly exacerbated atherosclerotic plaque development and post-MI cardiac remodeling. Conditional Vcam1 silencing in PCOS mice significantly suppressed cardiac inflammation and improved cardiac injury after MI. CONCLUSIONS: Our data documented previously unrecognized mechanisms through which PCOS could affect cardiovascular health in women. PCOS may promote myocardial macrophage accumulation and post-MI cardiac remodeling because of augmented splenic myelopoiesis.

Objective: Although numerous observational studies have revealed a correlation between leukocyte telomere length (LTL) and female reproductive system diseases (RSDs), the findings of these studies have tended to be consistent. In this study, we accordingly sought to clarify the causal relationships between LTL and RSDs. Methods: We performed a bidirectional two-sample Mendelian randomization (MR) analysis using pooled statistics from genome-wide association studies of LTL and nine female RSDs. The final results were analyzed using five MR methods, with the inverse variance weighted (IVW) method used as the primary outcome. We applied MR-PRESSO to exclude outliers. Sensitivity analyses were also conducted to assess heterogeneity and pleiotropy. Results: In the forward MR analysis, a genetic prediction of longer LTLs was found to be causally associated with higher risks of endometriosis (IVW: odds ratio [OR] = 1.25, 95% confidence interval [CI] = 1.06–1.46, P = 0.008), leiomyoma of the uterus (IVW: OR = 1.73, 95% CI = 1.52–1.98, P = 4.9E-16), and ovarian cysts (IVW: OR = 1.31, 95% CI:1.19–1.45, P = 1.5E-07). In the reverse MR results, female RSDs were shown to have no significant effect on LTLs (all P values >0.05). Sensitivity analysis confirmed the robustness of these results. Conclusions: Our findings substantiate the assumption that a genetically predicted longer LTL elevates the risk of endometriosis, leiomyoma of the uterus, and ovarian cysts, with no influence of RSDs on LTL. These findings contribute to establishing a causal link between LTL and RSDs, overcoming the constraints of earlier observational studies. They also imply that LTL could potentially serve as a biomarker for the occurrence of endometriosis, leiomyoma of the uterus, and ovarian cysts.

Gestational hyperglycemia (GHG) causes fetal growth restriction (FGR), while its mechanism remains incompletely understood. Defects in the syncytiotrophoblast, which is pivotal for maternal‐fetal substance exchange, adversely affect fetal development. Whether dysfunction in syncytiotrophoblast is involved in GHG‐related FGR remains unclear. In this study, we used an STZ‐induced GHG mouse model and found that GHG‐induced FGR (44.5% reduction in fetal weight) was associated with a 28.3% decrease in placental efficiency. Immunofluorescence and transmission electron microscopy examinations revealed defective formation of the syncytiotrophoblast layer in GHG placenta, resulting from impaired fusion of trophoblast cells. Gene expression profiling and staining analysis of the placenta revealed that Tim1 , a phosphatidylserine‐binding protein, was 43.5% downregulated in GHG placenta. In vitro studies confirmed that hyperglycemia decreased Tim1 and led to trophoblast fusion defects. Tim1 silence alone recapitulated the effects of hyperglycemia on trophoblast fusion, while Tim1 overexpression rescued the anti‐fusion effects of hyperglycemia. Moreover, we generated a Tim1 knockout mouse strain, and observed that Tim1 deficiency alone induced defective formation of syncytiotrophoblast and FGR during pregnancy. Further analysis revealed that Tim1 was downregulated by hyperglycemia‐related oxidative stress. Antioxidant treatment during pregnancy reversed Tim1 downregulation, promoted syncytiotrophoblast formation and improved FGR. Finally, the reduction of TIM1 expression was confirmed in human placenta with pre‐gestational diabetes and FGR. These findings suggest that Tim1 downregulation in GHG inhibits placental syncytiotrophoblast formation and contributes to FGR.

Polycystic ovary syndrome (PCOS) is one of the leading causes of infertility in women. Animal models are widely used to study the etiologic mechanisms of ... Jove