Hydrogen sulfide in placental development and pregnancy disorders: mechanisms, therapeutic potential, and translational challenges.

The placenta plays a crucial role in maintaining pregnancy stability, regulating fetal growth, and facilitating maternal-fetal exchange. Its proper development relies on placental vasculogenesis and angiogenesis, along with adaptive remodeling of the maternal uterine vasculature. However, the mechanisms underlying placental development and the successful establishment of the maternal-fetal interface remain incompletely understood. As the third gaseous signaling molecule identified after nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H₂S) has been demonstrated to regulate vascular adaptation during pregnancy by promoting angiogenesis and neovascularization. Dysregulated H₂S biosynthesis has been implicated in pregnancy complications, including preeclampsia (PE), fetal growth restriction (FGR), and preterm birth (PTB), underscoring its potential as a therapeutic target. Recent studies have revealed that H₂S regulates placental function via multiple signaling pathways, including activating adenosine triphosphate (ATP)-sensitive K⁺ (K_ATP) channels, large-conductance calcium-activated potassium channels (BK_Ca channels), endothelial nitric oxide synthase (eNOS) signaling, and mitochondrial dynamics. Notably, H₂S-mediated persulfidation of mitochondrial Rho GTPase 2 (Miro2) has been shown to maintain trophoblast invasiveness and promote placental vascular homeostasis. Additionally, exogenous H₂S donors (e.g., GYY4137 and NaHS) have demonstrated therapeutic potential in experimental models, effectively reversing PE-like pathologies, improving placental perfusion, and restoring trophoblast function. Research further indicates that BK_Ca channels play a key role in H₂S-mediated vasodilation by modulating intracellular Ca²⁺ flux, which influences placental vascular tone and perfusion, reinforcing the importance of H₂S in maternal-fetal circulation regulation. This review provides a comprehensive summary of H₂S biosynthesis and metabolism and its regulatory role in early placental development. Notably, elevated estrogen levels during pregnancy have been identified as key regulators of H₂S production, and we discuss the molecular mechanisms by which estrogen modulates H₂S synthesis. Furthermore, we discuss the vascular-protective and anti-inflammatory properties of H₂S donors and dual-donor strategies. As research continues to reveal H₂S-mediated mechanisms in placental function and pregnancy disorders, optimizing the pharmacological application and clinical translation of H₂S donors and combination therapies will be a key research focus. Advancing H₂S metabolic regulation, signaling pathways, and targeted delivery systems may drive the development of novel diagnostic tools and therapeutic strategies for pregnancy complications.