Early life stress induces transgenerational, age-dependent cardiac dysfunction through epigenetic activation of BMP10

Introduction Early life stress (ELS) in childhood due to physical or sexual violence, parental neglect, or trauma has been recently associated with an increased risk of cardiovascular disease in later life. However, the mechanisms linking ELS to cardiovascular impairment remain unexplored. Purpose To investigate whether ELS induces age-dependent and transgenerational cardiac dysfunction and to identify the underlying mechanisms. Methods ELS was induced using the maternal separation with unpredictable stress (MSUS) mouse model. From postnatal day (PND) 1-14, pups were separated daily for 3 hours, while dams underwent forced swim or restraint. Cardiac structure and function were assessed by echocardiography at 6,12, and 18 months in exposed parents (F0) and their offspring (F1, F2). Left ventricular tissue underwent RNA sequencing and single-nucleus RNA sequencing (snRNA-seq). Mechanistic studies were performed in adult cardiomyocytes and H9C2 cells, including chromatin immunoprecipitation (ChIP). Environmental enrichment (EE; larger cages with mazes) was tested as rescue strategy. Results MSUS induced progressive, age-dependent cardiac dysfunction characterised by increased LV mass, diastolic impairment, cardiomyocyte hypertrophy, fibrosis and lung congestion, emerging at 12-18 months and transmitted to F1 and F2 (Fig.1). RNA-seq revealed transcriptional reprogramming in MSUS hearts across generations. Bone morphogenetic protein 10 (BMP10) was the top consistently upregulated transcript. snRNA-seq showed predominant BMP10 expression in ventricular cardiomyocytes and significant upregulation in stressed mice. Circulating BMP10 levels were elevated in all generations, suggesting systemic stress imprinting. Pathway analysis linked BMP10 to activin receptor and SMAD signalling, thereby implicating it directly in stress-responsive transcriptional regulation within cardiac cells. Mechanistically, exposure of H9C2 cardiomyocytes to various stress-associated hormones robustly induced BMP10 expression. This induction was most pronounced under combined stress conditions and was consistently accompanied by a significant increase in hypertrophic and fibrotic gene transcription, underscoring BMP10 role in cardiac remodelling. Importantly, BMP10 knockdown attenuated these responses, supporting a causal role for BMP10 in stress-driven cardiac remodelling. ChIP revealed enhanced enrichment of activating histone marks at the BMP10 promoter in MSUS hearts, supporting epigenetic activation. Importantly, EE exposure rescued LV hypertrophy, diastolic dysfunction while normalising BMP10 levels (Fig.2). Conclusions ELS drives progressive, transgenerational cardiac dysfunction, mediated by cardiomyocyte BMP10 upregulation. Stress mitigating strategies such as EE attenuated BMP10 activation thus rescuing cardiac impairment. Our findings suggest that BMP10 could represent a new stress-related biomarker and therapeutic target in this setting.