Role of extracellular signal-regulated kinase and AKT cascades in regulating hypoxia-induced angiogenic factors produced by a trophoblast-derived cell line

Abstract

During human pregnancy, trophoblasts play an important role in embryo implantation and placental development. Cytotrophoblast cells invade the uterine spiral arteries and differentiate into extravillous trophoblasts, resulting in the remodeling of the uterine vessels and fetoplacental vasculature. During early pregnancy, a physiologically hypoxic environment induces the production of angiogenic factors, such as vascular endothelial growth factor (VEGF), which are suggested to locally control the vascular remodeling. Endoglin, a cell-surface coreceptor for transforming growth factor-b1, is highly expressed in endothelial cells and syncytiotrophoblasts, and can be associated with endothelial nitric oxide synthase and vascular homeostasis. Several studies have recently suggested that some pregnancy-related complications, such as preeclampsia, have their origins early in pregnancy as a result of abnormalities in implantation and placental development. Although angiogenic factors are recognized as key molecules in placental development, little is known about the mechanism(s) of their regulation in trophoblasts. In this study, we elucidated the mechanisms underlying the regulation of VEGF and endoglin production under hypoxic conditions in the trophoblast-derived cell line, BeWo. We evaluated the role of the AKT-MTOR cascade and ERK kinase in the expression of VEGF and endoglin in response to hypoxia using various kinase inhibitors and small interfering RNA targeted against hypoxia-inducible factor (HIF)-1a (listed as HIF1A in Hugo Database). Our results suggest that both the phosphatidylinositol 3-kinase-AKT-MTOR-HIF-1a and ERK-HIF-1a signaling pathways are crucial for increasing VEGF and endoglin expression in response to hypoxia in BeWo cells.

Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management

“…51 Endoglin is a transforming growth factor-b (TGF-b) co-receptor expressed mainly in proliferating endothelial cells and in conjunction with VEGF and PD-ECGF; these factors regulate angiogenesis and vascular remodeling, processes essential for tumor formation and maintenance. 38,62,86 Furthermore, VEGF expression is dramatically increased in malignant SHN-PG, which is indicative of its role in potential malignant transformation. 89 Increased levels of these proteins also provide an explanation for the robust vascularity associated with with paragangliomas and why bleeding is among the biggest challenges in surgical control.…”

“…Activation of HRE results in the transcription of different pathways relevant to tumorigenesis, as well as other hypoxia-driven physiological compensatory pathways, such as pH regulation, glucose metabolism, and erythropoiesis. 33,100 Among the proteins that have increased expression resulting from activation of HRE by the HIF-1-a/b complex are endoglin (ENG), vascular endothelial growth factor (VEGF), 9,38,51,80,89 and platelet-derived endothelial cell growth factor (PD-ECGF). 51 Endoglin is a transforming growth factor-b (TGF-b) co-receptor expressed mainly in proliferating endothelial cells and in conjunction with VEGF and PD-ECGF; these factors regulate angiogenesis and vascular remodeling, processes essential for tumor formation and maintenance.…”

Inhibition of Akt Activity and Calcium Channel Function Coordinately Drive Cell-Cell Fusion in the BeWO Choriocarcinoma Placental Cell Line

“…Proteins were visualized with the Odyssey Infrared Imaging System (LI-COR Biosciences, Lincoln, NE, USA). Induction of Akt phosphorylation, as a measure of Akt activation, was accomplished by incubating the BeWo cells in hypoxic conditions as previously described [25].…”

Insights into the mechanism of CXCL12-mediated signaling in trophoblast functions and placental angiogenesis

“…When stimulated by hypoxia, placental tissue cells such as trophoblasts, DSCs, and endothelial cells produce HIF-1α to adapt to the low oxygen environment [55], which in turn up-regulates the pro-angiogenic factors, including VEGF, CXCL12, PLGF, FGF-2, and angiopoietin-1 [27,71]. Stimulation of trophoblasts by hypoxia also activates the PI3K/AKT/mTOR and ERK1/2 signaling pathways and leads to enhanced expressions of CXCL12, VEGF, FGF-2, and endoglin [71,72]. Furthermore, HIF-1α-induced recruitment of endothelial progenitor cells may be Figure 2.…”

“…Thus, HIF-1α plays a vital role in placental angiogenesis, and may serve as an upstream inducer of the CXCL12/CXCR4 axis, as well as VEGF signaling, to promote placental angiogenesis during early pregnancy [55,72].…”