Decreased expression of the HDAC2 disrupts the SLIT-ROBO signaling pathway and induced angiogenesis in placental endothelial cells in preeclampsia

Abstract Background: Preeclampsia is characterized by reduced histone deacetylase 2 (HDAC2) expression in placental tissue HDAC2 enrichment positively affects angiogenesis as it helps prevent endothelial cell dysfunction. Additionally, research has demonstrated that the SLIT2-ROBO signaling pathway influences preeclampsia. Bioinformatics analysis has suggested that HDAC2 may have a transcriptional regulatory effect on SLIT2. Consequently, investigations have examined the relationship between low HDAC2 expression and the SLIT-ROBO signaling pathway in placental angiogenesis in patients with preeclampsia. Objective: To investigate how decreased HDAC2 expression disrupts the SLIT-ROBO signaling pathway and induces angiogenesis in placental endothelial cells in preeclampsia. Methods:The study included patients with preeclampsia as the observation group, while the placental tissue of normal pregnant women was used as the in vivo control model. In vitro endothelial models using human umbilical veins and microvascular endothelial cells were also used to examine the effects of interference with the expression of HDAC2 and SLIT2. Cell viability CCK-8, colony formation, and tube formation assays were conducted to evaluate angiogenesis. Furthermore, Immunohistochemistry, RT-qPCR, and Western blot analyses were used to examine the expression of genes in cells and tissues. Results: The expression of SLIT2 and ROBO1 was increased, and the protein and mRNA expression of CD34, HDAC2, and vonWillebrand factor(vWF) were lower in preeclampsia placentas than in normal placentas. Using an in vitro endothelial model, the knockdown of HDAC2 inhibited colony formation and impaired neovascularization by reducing vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor -2 (VEGFR2) activity, while SLIT2 and ROBO1 were highly expressed. The changes caused by HDAC2 knockdown were reversed by SLIT2 knockdown. Conclusion: Preeclampsia progression is promoted by low HDAC2 expression, which inhibits the SLIT-ROBO signaling pathway and induces angiogenesis in placental endothelial cells.