Therapeutics Discovery and Vascular Function in Pregnancy Group (B.R.F., N.d.A., S.B., N.K.B., N.J.H.), University of Melbourne, Heidelberg, Victoria, Australia.
Department of Obstetrics, Gynecology and Newborn Health, Mercy Hospital for Women (B.R.F., N.d.A., S.B., N.K.B., N.P., T.J.K.-L., N.J.H.), University of Melbourne, Heidelberg, Victoria, Australia.
Hypertension. 2024 Sep;81(9):1883-1894. doi: 10.1161/HYPERTENSIONAHA.124.22820. Epub 2024 Jul 17.
Preeclampsia is a serious condition of pregnancy, complicated by aberrant maternal vascular dysfunction. CNP (C-type natriuretic peptide) contributes to vascular homeostasis, acting through NPR-B (natriuretic peptide receptor-B) and NPR-C (natriuretic peptide receptor-C). CNP mitigates vascular dysfunction of arteries in nonpregnant cohorts; this study investigates whether CNP can dilate maternal arteries in ex vivo preeclampsia models.
Human omental arteries were dissected from fat biopsies collected during cesarean section. CNP, NPR-B, and NPR-C mRNA expression was assessed in arteries collected from pregnancies complicated by preeclampsia (n=6) and normotensive controls (n=11). Using wire myography, we investigated the effects of CNP on dilation of arteries from normotensive pregnancies. Arteries were preconstricted with either serum from patients with preeclampsia (n=6) or recombinant ET-1 (endothelin-1; vasoconstrictor elevated in preeclampsia; n=6) to model vasoconstriction associated with preeclampsia. Preconstricted arteries were treated with recombinant CNP (0.001-100 µmol/L) or vehicle and vascular relaxation assessed. In further studies, arteries were preincubated with NPR-B (5 µmol/L) and NPR-C (10 µmol/L) antagonists before serum-induced constriction (n=4-5) to explore mechanistic signaling.
CNP, NPR-B, and NPR-C mRNAs were not differentially expressed in omental arteries from preeclamptic pregnancies. CNP potently stimulated maternal artery vasorelaxation in our model of preeclampsia (using preeclamptic serum). Its vasodilatory actions were driven through the activation of NPR-B predominantly; antagonism of this receptor alone dampened CNP vasorelaxation. Interestingly, CNP did not reduce ET-1-driven omental artery constriction.
Collectively, these data suggest that enhancing CNP signaling through NPR-B offers a potential therapeutic strategy to reduce systemic vascular constriction in preeclampsia.
子痫前期是一种严重的妊娠并发症，伴有母体血管功能异常。CNP（C 型利钠肽）通过 NPR-B（利钠肽受体-B）和 NPR-C（利钠肽受体-C）参与血管稳态。CNP 减轻非妊娠队列中动脉的血管功能障碍；本研究调查 CNP 是否可以扩张子痫前期的离体母体动脉模型。
从剖宫产术中收集的脂肪活检中分离出人脐动脉。评估来自子痫前期（n=6）和正常血压对照（n=11）妊娠的动脉中 CNP、NPR-B 和 NPR-C mRNA 的表达。使用线描记法，我们研究了 CNP 对正常妊娠动脉扩张的影响。用子痫前期患者的血清（n=6）或重组 ET-1（内皮素-1；在子痫前期中升高的血管收缩剂；n=6）预收缩动脉来模拟与子痫前期相关的血管收缩。用重组 CNP（0.001-100μmol/L）或载体处理预收缩的动脉，并评估血管舒张。在进一步的研究中，在用血清诱导收缩之前，用 NPR-B（5μmol/L）和 NPR-C（10μmol/L）拮抗剂预孵育动脉（n=4-5），以探索机制信号。
CNP、NPR-B 和 NPR-C mRNA 在子痫前期脐动脉中无差异表达。CNP 在我们的子痫前期模型中强烈刺激母体动脉血管舒张（使用子痫前期血清）。其血管舒张作用主要通过 NPR-B 的激活驱动；仅拮抗该受体就会减弱 CNP 的血管舒张作用。有趣的是，CNP 不能减轻 ET-1 驱动的脐动脉收缩。
总的来说，这些数据表明，通过 NPR-B 增强 CNP 信号可能是减少子痫前期全身血管收缩的潜在治疗策略。
