Therapeutics Discovery & Vascular Function Group, Department of Obstetrics and Gynaecology, The University of Melbourne, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia.
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia.
Int J Mol Sci. 2022 Jul 25;23(15):8185. doi: 10.3390/ijms23158185.
Preeclampsia is a devastating, multisystem disorder of pregnancy. It has no cure except delivery, which if premature can impart significant neonatal morbidity. Efforts to repurpose pregnancy-safe therapeutics for the treatment of preeclampsia have led to the assessment of the proton pump inhibitor, esomeprazole. Preclinically, esomeprazole reduced placental secretion of anti-angiogenic sFlt-1, improved endothelial dysfunction, promoted vasorelaxation, and reduced maternal hypertension in a mouse model. Our understanding of the precise mechanisms through which esomeprazole works to reduce endothelial dysfunction and enhance vasoreactivity is limited. Evidence from earlier studies suggested esomeprazole might work via the nitric oxide pathway, upregulating endothelial nitric oxide synthase (eNOS). Here, we investigated the effect of esomeprazole in a mouse model of L-NAME-induced hypertension (decreased eNOS activity). We further antagonised the model by addition of diet-induced obesity, which is relevant to both preeclampsia and the nitric oxide pathway. Esomeprazole did not decrease blood pressure in this model, nor were there any alterations in vasoreactivity or changes in foetal outcomes in lean mice. We observed similar findings in the obese mouse cohort, except esomeprazole treatment enhanced ex vivo acetylcholine-induced vasorelaxation. As acetylcholine induces nitric oxide production, these findings hint at a function for esomeprazole in the nitric oxide pathway.
子痫前期是一种严重的多系统妊娠疾病。除了分娩，别无他法可以治愈，而早产可能会导致新生儿严重发病。人们尝试将妊娠安全的治疗药物重新用于子痫前期的治疗，从而评估质子泵抑制剂埃索美拉唑。在临床前，埃索美拉唑减少了胎盘分泌的抗血管生成 sFlt-1，改善了内皮功能障碍，促进了血管舒张，并减轻了小鼠模型中的母体高血压。我们对埃索美拉唑降低内皮功能障碍和增强血管反应性的确切机制的理解有限。早期研究的证据表明，埃索美拉唑可能通过一氧化氮途径发挥作用，上调内皮型一氧化氮合酶 (eNOS)。在这里，我们在 L-NAME 诱导的高血压（eNOS 活性降低）的小鼠模型中研究了埃索美拉唑的作用。我们进一步通过添加饮食诱导的肥胖来拮抗该模型，肥胖与子痫前期和一氧化氮途径都有关。埃索美拉唑在该模型中并未降低血压，也没有改变血管反应性或改变瘦小鼠的胎儿结局。我们在肥胖小鼠队列中观察到了类似的发现，除了埃索美拉唑治疗增强了体外乙酰胆碱诱导的血管舒张。由于乙酰胆碱会诱导一氧化氮的产生，这些发现提示埃索美拉唑在一氧化氮途径中具有作用。
