Low oxygen tension differentially regulates the expression of placental solute carriers and ABC transporters

Abstract

Low oxygen concentration, or hypoxia, is an important physiological regulator of placental function including chemical disposition. Here, we compared the ability of low oxygen tension to alter the expression of solute carriers (SLC) and ABC transporters in two human placental models, namely BeWo cells and term placental explants. We found that exposure to low oxygen concentration differentially regulates transporter expression in BeWo cells, including downregulation of ENT1, OATP4A1, OCTN2, BCRP, and MRP2/3/5, and upregulation of CNT1, OAT4, OATP2B1, SERT, SOAT, and MRP1. Similar upregulation of MRP1 and downregulation of MRP5 and BCRP were observed in explants, whereas uptake transporters were decreased or unchanged. Furthermore, a screening of transcriptional regulators of transporters revealed that hypoxia leads to a decrease in the mRNA levels of aryl hydrocarbon receptor, nuclear factor erythroid 2‐related factor 2, and retinoid x receptor alpha in both human placental models. These data suggest that transporter expression is differentially regulated by oxygen concentration across experimental human placental models.

Transporter Regulation in Critical Protective Barriers: Focus on Brain and Placenta

“…Changes in oxygen tension within the placental circulation also occur throughout pregnancy, and this can be affected by maternal conditions such as preeclampsia. Studies in cultured placental explants and BeWo cells have shown that hypoxia alters expression of a number of transporters including BCRP, P-gp, OATP2B1, and several MRPs [ 180 , 187 ]. Hypoxic conditions were also found to impact expression of regulatory nuclear factors involved in transporter regulation, including the Aryl hydrocarbon receptor (AHR), Nuclear factor erythroid 2-related factor 2 (NRF2), and Retinoid X receptor alpha (RXR-α) [ 187 ].…”

“…Studies in cultured placental explants and BeWo cells have shown that hypoxia alters expression of a number of transporters including BCRP, P-gp, OATP2B1, and several MRPs [ 180 , 187 ]. Hypoxic conditions were also found to impact expression of regulatory nuclear factors involved in transporter regulation, including the Aryl hydrocarbon receptor (AHR), Nuclear factor erythroid 2-related factor 2 (NRF2), and Retinoid X receptor alpha (RXR-α) [ 187 ]. Endogenous signaling proteins affecting growth or angiogenesis, such as the epidermal growth factor, insulin growth factor, and the soluble fms-like tyrosine kinase-1 (sFlt-1), have been shown to regulate BCRP [ 28 , 174 , 181 , 188 ].…”

“…Its etiology is poorly understood but the most accepted theories, according to the current evidence, describe the pathogenesis of the disease as a defective spiral artery remodeling that leads to placental ischemia, imbalance between antiangiogenic and proangiogenic factors, immune activation, and endothelial dysfunction (reviewed in [ 197 , 198 ]). The resulting increase in systemic levels of proinflammatory cytokines as well as placental hypoxia have each been shown to impact transporter regulation [ 181 , 187 , 192 ]. Indeed, changes in expression of numerous transporters along with alterations in transcript levels of cytokines and growth factors were seen in placenta obtained from women with preeclampsia [ 170 , 174 ].…”

The incredible diversity of structures and functions of ABC transporters

“…Transporter systems are adapted to the environment through diverse regulatory mechanisms—often linking multiple transporters into coordinately regulated networks. Examples of these networks are revealed in placental development where environmental signals such as hypoxia can alter levels of multiple transporters simultaneously [29].…”

3D-Printed Magnesium Peroxide-Incorporated Scaffolds with Sustained Oxygen Release and Enhanced Photothermal Performance for Osteosarcoma Multimodal Treatments

“…Contrastingly, the local hypoxic environment can boost the development, invasion, and tumor cell metastasis, and a chronic hypoxic environment confers resistance to chemotherapy. − Accordingly, alleviating local hypoxia is instrumental in improving the antitumor effect. In addition, oxygen concentration can also affect the repair of bone defects after osteosarcoma excision .…”