Abstract
Preeclampsia (PE), a severe pregnancy-specific syndrome, is characterized by impaired placental angiogenesis. Although the pathogenesis of this condition remains largely unclear, vascular systemic endothelial injury is thought to be the common contributing factor. Soluble Axl (sAxl), a biomarker of endothelial dysfunction, is known to be abnormally increased in a variety of diseases associated with vascular injury. In a previous study, we found that the plasma levels of sAxl were significantly higher in PE with severe features (sPE) than in pregnant women who did not have PE. The current study aimed to further explore the potential role of sAxl in vascular injury in patients with sPE. We found that the upregulation of sAxl in maternal plasma was positively correlated with the plasma levels of sFlt-1 and negatively correlated with placental NO synthase (eNOS) in women with sPE. Furthermore, elevated levels of sAxl suppressed proliferation and endothelial tube formation and promoted cytotoxicity in human umbilical vein endothelial cells (HUVECs) through the downregulation of p-Akt, p-p70S6K, p-mTOR, and Grb2. Subsequently, we established a pregnant rat model with PE-like characteristics by injecting pregnant rats with an adenovirus expressing sAxl. These rats exhibited a typical PE-like phenotype, including increased blood pressure, proteinuria, and fetal growth restriction, along with abnormal placental and fetal renal morphology. In conclusion, our study demonstrated the role of sAxl in systemic vascular injury through the regulation of the expression of key molecules of angiogenesis and described its potential contribution to the development of sPE.
Highlights
Preeclampsia (PE), as one of the main causes of maternal and perinatal mortality, represents a significant threat to the health of both the mother and the fetus (Mol et al, 2016)
The results are presented as the mean ± SD. **Represents pregnant women with preeclampsia and severe features or pre-term pregnancy group compared with term pregnancy group, **P < 0.01
For the first time to our knowledge, this study showed that increased levels of Soluble Axl (sAxl) had cytotoxicity effects sAxl May Cause Vascular Endothelial Cell Damage on endothelial cells
Summary
Preeclampsia (PE), as one of the main causes of maternal and perinatal mortality, represents a significant threat to the health of both the mother and the fetus (Mol et al, 2016). In pregnant women with PE, an excess of sFlt-1 is secreted by the placenta, which binds to local and circulating vascular endothelial growth factor (VEGF) and PlGF, resulting in the inhibition of VEGF and PlGF signaling in the vasculature (Phipps et al, 2019). This inhibition state subsequently impacts endothelial cell dysfunction, including the reduced production of nitric oxide (NO), prostacyclin, and the release of procoagulant proteins. The anti-angiogenic protein further reduced the activity of endothelial NO synthase (eNOS), resulting in reduced NO availability and increased vascular permeability, which leads to systemic vascular dysfunction (Venkatesha et al, 2006)
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