Effect of Oxidative Stress on the Estrogen-NOS-NO-K_Ca Channel Pathway in Uteroplacental Dysfunction: Its Implication in Pregnancy Complications

Figure 1

Estrogen (E₂β) regulates uterine artery function partly via its actions on endothelial nitric oxide synthase (eNOS) in the endothelial cell (EC) and the large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel in vascular smooth muscle cell (VSMC) during pregnancy. Shear stress stimulates eNOS activity, leading to increased NO production. E₂β could increase the expression of eNOS in ECs via interacting with nuclear estrogen receptors (ERs) and/or elevate eNOS activity via interacting with the G protein-coupled estrogen receptor (GPER, GPR30) or membrane-associated ERα and ERβ. In addition, E₂β increases the expression of the BK_Ca channel β1 subunit encoded by KCNMB1 and channel activity via upregulating ten-eleven translocation methylcytosine dioxygenase 1 (TET1, encoded by TET1) in VSMCs. Moreover, the activity of the BK_Ca channel can be enhanced by NO-PKG signaling. In pregnancy complications, excessive oxygen species (ROS) impair the estrogen-NOS-NO-BK_Ca channel pathway.