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.Preeclampsia: when cells aren’t invasive enoughCancer-associated proteins play a role in preeclampsia, a potentially life-threatening disorder of pregnancy marked by high blood pressure and protein in the urine. The causes of preeclampsia are poorly understood, but the tissue that nourishes the fetus, the placenta, is known to be involved. Knowing that for healthy placenta formation, cells called trophoblasts must show cancer cell-like behavior and invade the developing tissue, Li-Ping Jin and Kai Wang at Tongji University School of Medicine in Shanghai, China, and co-workers investigated the role of cancer-associated LOX proteins, previously linked to cell invasiveness. Preeclamptic placentas showed low LOX levels, poor trophoblast invasion, and excessive formation of collagen, an important connective tissue. Further analysis showed that this excessive collagen is broken down, becoming the diagnostic urinary protein. These results illuminate potential markers for early diagnosis and treatment of preeclampsia.