Collagen I Induces Preeclampsia-Like Symptoms by Suppressing Proliferation and Invasion of Trophoblasts

Abstract

Preeclampsia is a common obstetric disorder affecting 2-8% of pregnancy worldwide. Fibrosis is an important histological change occurring in preeclamptic placenta, and might depend on the excess deposition of collagen I. However, the role of fibrotic placenta and collagen I in the pathogenesis of preeclampsia remains unclear. Therefore, we analyzed the collagen deposition and the expression of Collagen I in human placenta by Masson staining, Sirius red staining and western blotting. Further, the role of collagen I in preeclampsia pathogenesis was studied in C57BL/6 mice. HTR-8/SVneo cells were used to investigate the mechanisms underlying the effects of collagen I in trophoblasts by transcriptome sequencing and pharmacological agonists. Human preeclamptic placenta exhibited a significantly higher degree of fibrosis in stem villi and terminal villi than normal placenta, and was characterized by collagen I deposition. In vivo, a single injection of collagen I on gestational day 0.5 led to an increase in systolic pressure of pregnant mice from gestational days 4.5–17.5, to a decrease in weight and number of embryos, and to enhanced placental collagen I expression and degree of fibrosis compared with control mice. In vitro, collagen I attenuated the proliferation and invasion of HTR-8SV/neo cells. This effect could be reversed by treatment with agonists of ERK and β-catenin. Moreover, transcriptome sequencing demonstrated that signaling pathways related to cell proliferation and invasion were significantly downregulated in HTR-8SV/neo cells. Thus, we propose that collagen I induced preeclampsia-like symptoms by suppressing the proliferation and invasion of trophoblasts through inhibition of the ERK phosphorylation and WNT/β-catenin signaling pathways. Our findings could pave the way to the discovery of small-molecule inhibitors for preeclampsia treatment and future studies with larger sample size are required.

Oxidative and Inflammatory Imbalance in Placenta and Kidney of sFlt1-Induced Early-Onset Preeclampsia Rat Model

“…Thus, morphological alterations have been reported in both the placenta and kidney under preeclamptic conditions [ 36 , 37 ], and histopathological examination of the kidney has been suggested as a predictive tool for prognostic purposes [ 38 ]. Collagen deposition in the placenta has been found in the reduced uteroplacental perfusion pressure (RUPP) preeclampsia animal model [ 39 ], and excess collagen deposition originated preeclampsia-like features in pregnant mice [ 40 ]. Interestingly, serum from PE patients has been shown to contain vasoactive substances that induce deposition of extracellular matrix components including collagen [ 41 ].…”

Preeclampsia Correlates with an Increase in Cannabinoid Receptor 1 Levels Leading to Macromolecular Alterations in Chorionic Villi of Term Placenta

“…As mentioned above, impaired trophoblast proliferation and migration can lead to improper remodeling of maternal spiral arteries, which is one of the main factors contributing to preeclampsia. It is noteworthy that an excess of collagen I led to preeclampsia-like features in pregnant mice since it suppresses trophoblast proliferation and invasion through inhibition of ERK phosphorylation and the WNT/β-catenin signaling pathway [ 43 ]. These authors also reported an increase in the collagen I deposition as well as a higher gene and protein expression of collagen in the preeclamptic placenta [ 43 ].…”

“…It is noteworthy that an excess of collagen I led to preeclampsia-like features in pregnant mice since it suppresses trophoblast proliferation and invasion through inhibition of ERK phosphorylation and the WNT/β-catenin signaling pathway [ 43 ]. These authors also reported an increase in the collagen I deposition as well as a higher gene and protein expression of collagen in the preeclamptic placenta [ 43 ]. Collagen deposition has also been evaluated in first-term villi and full-term placentas, and the results obtained by Masson’s trichrome staining and western blot also showed higher levels of collagen in preeclampsia patients [ 44 ].…”

Red Light Mitigates the Deteriorating Placental Extracellular Matrix in Late Onset of Preeclampsia and Improves the Trophoblast Behavior

“…The development of placental fibrosis in preeclampsia is a well-studied process [ 24 , 25 ]. Collagen-I deposition is increased in fibrosis leading to preeclampsia [ 26 ]. Collagen-I expression was increased in our late-onset preeclampsia samples compared to our healthy placental samples suggesting an increase in fibrosis.…”