Serpin family E member 1 enhances myometrium contractility by increasing ATP production during labor

The uterine contraction during labor, a process with repetitive hypoxia and high energy consumption, is essential for successful delivery. However, the molecular mechanism of myometrial contraction regulation is unknown. Serpin family E member 1 (SERPINE1), one of the most upregulated genes in laboring myometrium in both transcriptome and proteome, was highlighted in our previous study. Here, we confirmed SERPINE1 is upregulated in myometrium during labor. Blockade of SERPINE1 using small interfering RNA (siRNA) or inhibitor (Tiplaxtinin) under hypoxic conditions in myocytes or myometrium in vitro showed a decrease contractility, which was achieved by regulating ATP production. Chromatin immunoprecipitation (ChIP‐seq), Co‐immunoprecipitation (Co‐IP), and glutathione‐S‐transferase (GST) pull down explored that the promoter of SERPINE1 is directly activated by hypoxia‐inducible factor‐1α (HIF‐1α) and SERPINE1 interacts with ATP Synthase Peripheral Stalk Subunit F6 (ATP5PF). Together they enhance hypoxia driven myometrial contraction by maintaining ATP production in the key oxidative phosphorylation pathway. The results provide new insight for uterine contraction regulation, and potential novel therapeutic targets for labor management. This study demonstrated that SERPINE1 is upregulated in laboring myometrium, and enhances hypoxia driven myometrial contractility. The mechanisms of interaction between SERPINE1 and its up/downstream molecules were found in hMSMCs: (1) SERPINE1 promotes ATP production, especially oxidative phosphorylation; (2) HIF‐1α (hypoxia‐inducible factor) directly activates SERPINE1; (3) SERPINE1 stabilizes ATP5PF (a component of mitochondrial ATP synthase) activity. The evidence clarifies the energy supply mechanism to maintain myometrial contraction during labor and may become a therapeutic target for delivery management.