Downregulation of lysyl oxidase and lysyl oxidase-like protein 2 suppressed the migration and invasion of trophoblasts by activating the TGF-β/collagen pathway in preeclampsia

Abstract

Preeclampsia is a pregnancy-specific disorder that is a major cause of maternal and fetal morbidity and mortality with a prevalence of 6–8% of pregnancies. Although impaired trophoblast invasion in early pregnancy is known to be closely associated with preeclampsia, the underlying mechanisms remain elusive. Here we revealed that lysyl oxidase ( LOX ) and LOX-like protein 2 ( LOXL2 ) play a critical role in preeclampsia. Our results demonstrated that LOX and LOXL2 expression decreased in preeclamptic placentas. Moreover, knockdown of LOX or LOXL2 suppressed trophoblast cell migration and invasion. Mechanistically, collagen production was induced in LOX - or LOXL2 -downregulated trophoblast cells through activation of the TGF-β1/Smad3 pathway. Notably, inhibition of the TGF-β1/Smad3 pathway could rescue the defects caused by LOX or LOXL2 knockdown, thereby underlining the significance of the TGF-β1/Smad3 pathway downstream of LOX and LOXL2 in trophoblast cells. Additionally, induced collagen production and activated TGF-β1/Smad3 were observed in clinical samples from preeclamptic placentas. Collectively, our study suggests that the downregulation of LOX and LOXL2 leading to reduced trophoblast cell migration and invasion through activation of the TGF-β1/Smad3/collagen pathway is relevant to preeclampsia. Thus, we proposed that LOX , LOXL2 , and the TGF-β1/Smad3/collagen pathway can serve as potential markers and targets for clinical diagnosis and therapy for preeclampsia.

Low oxygen enhances trophoblast column growth by potentiating differentiation of the extravillous lineage and promoting LOX activity

“…Although a role of LOX in column formation has not been previously reported, the importance of LOX in tumourigenesis is known, in which elevated LOX associates with numerous types of cancers and LOX activity promotes tumour cell metastasis (Cox et al, 2015;Di Stefano et al, 2016). Further, previous reports do provide evidence that LOX expression is restricted to column trophoblasts (Segond et al, 2013) and promotes cell invasion of a trophoblast cell line (Xu et al, 2019). This later finding is consistent with the association of LOX expression and the EVT phenotype.…”

Lysyl Oxidase (LOX): Functional Contributions to Signaling Pathways

“…In testing trophoblast cells, knockdown of LOX suppressed cell migration and invasion with activation of the TGF-β /SMAD3 pathway. This effect could be rescued by inhibiting the TGF-β/SMAD3 pathways, known to be active not only in cells, but also in clinical samples [ 40 ].…”

Linking LOXL2 to Cardiac Interstitial Fibrosis

“…Although differentiation between the various isoforms is still unclear, LOX is known to promote collagen and elastin cross-linking by oxidatively deaminating the lysine and hydroxylysine groups within the peptide chains [ 46 ]. In addition, LOX is implicated in the transcriptional regulation of transforming growth factor beta (TGF-β) signaling [ 47 ]. Increased TGF-β is known to upregulate of alpha smooth muscle actin (α-SMA) leading to excessive cardiac scar formation with enhanced fibrosis [ 36 , 48 ].…”