Long-term impacts of preeclampsia on the cardiovascular system using murine models

Abstract

Preeclampsia (PE) is a multisystemic pregnancy disorder accounting for 76,000 maternal and 500,000 perinatal deaths annually, often leaving survivors with severe long-term complications. Angiogenic imbalance and compromised protective pathways are implicated in PE pathogenesis. Soluble fms-like tyrosine kinase 1 (sFlt-1), a soluble form of the vascular endothelial growth factor receptor 1 (VEGFR-1) extracellular ligand-binding domain, a crucial anti-angiogenic factor released by the placenta, plays vital role in PE pathogenesis. Hydrogen Sulphide (H2S), an endogenous gaseous transmitter, is a potent vessel dilater, responsible for cellular physiology. Cystathionine-g-lyase (CSE) is the main enzyme in cardiovascular system to produce H2S. Its Dysregulation is associated with PE. sFlt-1 overexpression and CSE malfunction have been used to induce PE-like symptoms in mice. However, the long-term impact on cardiovascular outcomes post-PE in these models remains unclear. We hypothesized that sFlt-1 induces PE-like symptoms and cardiovascular maladaptations during pregnancy and leads to long-term cardiovascular dysfunction. Using echocardiography, we found that pregnancy induced cardiovascular adaptations took place in mice treated with adenovirus empty vector (AdCMV). While as in sFlt-1 overexpressing pregnant mice, these adaptions were compromised alongside with PE-like symptoms, increased arterial pressure and reduced foetal weight. Furthermore, the cardiac dysfunction persisted beyond the immediate postpartum. We also investigated the role of CSE in the maternal cardiovascular adaptation. Echocardiography revealed that compared to CSE wild-type (CSE WT), pregnancy induced cardiac adaptation was compromised and associated with increased mitochondrial DNA content. Finally, significant differences in the gene profiles in sFlt-1 overexpressing mice during pregnancy and postpartum were identified using RNA sequencing, suggesting exposure of sFlt-1 has long-term consequences in cardiovascular system. In conclusion, our research enhances the understanding of the immediate and enduring effects of sFlt-1 and the underlying mechanisms of PE attributable to H2S dysregulation.