The Impact of Hydroxychloroquine on Primary Feto-Placental Endothelial Cells from Healthy and Early-Onset Preeclamptic Placentas

Abstract

Hydroxychloroquine (HCQ), an anti-malarial drug, is suggested as a promising candidate for the treatment of pregnancy-related disorders associated with endothelial activation, among which there is preeclampsia (PE). Arterial feto-placental endothelial cells (fpECAs) were isolated from control (CTR) and early-onset preeclamptic (EO-PE) placentas. The aim of this study was to test potential protective effects of HCQ in an in vitro model of endothelial activation as well as in cells isolated from EO-PE placentas. To mimic PE conditions, CTR fpECAs were exposed to a pro-inflammatory environment consisting of tumor necrosis factor α (TNF-α), interleukin (IL)-6 and IL-1β (furtherly referred as MIX) with or without varying concentrations of HCQ (1 µg/mL and 10 µg/mL). Their effect on wound healing and endothelial barrier integrity was analyzed. Variations in the expression of IL-8 and leukocyte adhesion molecules (LAM) on both mRNA and protein levels were determined between CTR and PE fpECAs in the presence or absence of HCQ. MIX decreased wound healing and stability of the endothelial barrier, but HCQ did not affect it. Significant differences between CTR and EO-PE fpECAs were observed in IL-8 mRNA, protein secretion, and vascular cell adhesion protein 1 (VCAM-1) mRNA expression levels. After challenging CTR fpECAs with MIX, upregulation of both mRNA and protein levels was observed in all molecules. Combined treatment of HCQ and MIX slightly lowered VCAM-1 total protein amount. In CTR fpECAs, treatment with low concentrations of HCQ alone (1 µg/mL) reduced basal levels of IL-8 and VCAM-1 mRNA and secretion of IL-8, while in EO-PE fpECAs, a higher (10µg/mL) HCQ concentration slightly reduced the gene expression of IL-8. Conclusion: These results provide additional support for the safety of HCQ, as it did not adversely affect endothelial functionality in control fpECAs at the tested concentration. Furthermore, the observed limited effects on IL-8 secretion in EO-PE fpECAs warrant further investigation, highlighting the need for clinical trials to assess the potential therapeutic effects of HCQ in preeclampsia. Conducting clinical trials would offer a more comprehensive understanding of HCQ’s efficacy and safety, allowing us to explore its potential benefits and limitations in a real-world clinical setting.

Deciphering the immunological interactions: targeting preeclampsia with Hydroxychloroquine’s biological mechanisms

“…For instance, in high-glucose conditions, HCQ decreased ROS production in endothelial cells but also diminished NO production and angiogenesis ( Rezabakhsh et al, 2017 ). Conversely, when exposed to a mixture of pro-inflammatory cytokines, HCQ did not affect angiogenesis in fetal arterial endothelial cells ( Gajić et al, 2023 ), while in the presence of just TNF-α, HCQ improved angiogenesis in HUVECs ( Rahman et al, 2016 ).…”

“…Although HCQ cannot directly protect cells from cytokine storms ( Gajić et al, 2023 ), it could indirectly decrease their overall production them. We have already discussed in previous chapters how HCQ could influence cytokine production by TLRs modulation.…”

“…It has been shown that HCQ induces a decline of VCAM-1 in endothelial cells ( Le et al, 2014 ; Li et al, 2018 ; Hu Y. et al, 2022 ; Kadife et al, 2022 ; Gajić et al, 2023 ). It has been suggested that this inhibition goes through the activation of ERK5 ( Le et al, 2014 ; Cheng et al, 2018 ).…”