de Wijs-Meijler Daphne P M, Danser A H Jan, Reiss Irwin K M, Duncker Dirk J, Merkus Daphne
Division of Experimental Cardiology, Department of Cardiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
Division of Neonatology, Department of Pediatrics, Sophia Children's Hospital Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
Physiol Rep. 2017 Jun;5(11). doi: 10.14814/phy2.13200.
Although the incidence of pulmonary hypertension is higher in females, the severity and prognosis of pulmonary vascular disease in both neonates and adults have been shown to be worse in male subjects. Studies of sex differences in pulmonary hypertension have mainly focused on the role of sex hormones. However, the contribution of sex differences in terms of vascular signaling pathways regulating pulmonary vascular function remains incompletely understood. Consequently, we investigated pulmonary vascular function of male and female swine in vivo, both at rest and during exercise, and in isolated small pulmonary arteries in vitro, with a particular focus on the NO-cGMP-PDE5 pathway. Pulmonary hemodynamics at rest and during exercise were virtually identical in male and female swine. Moreover, NO synthase inhibition resulted in a similar degree of pulmonary vasoconstriction in male and female swine. However, NO synthase inhibition blunted bradykinin-induced vasodilation in pulmonary small arteries to a greater extent in male than in female swine. PDE5 inhibition resulted in a similar degree of vasodilation in male and female swine at rest, while during exercise there was a trend towards a larger effect in male swine. In small pulmonary arteries, PDE5 inhibition failed to augment bradykinin-induced vasodilation in either sex. Finally, in the presence of NO synthase inhibition, the pulmonary vasodilator effect of PDE5 inhibition was significantly larger in female swine both in vivo and in vitro. In conclusion, the present study demonstrated significant sex differences in the regulation of pulmonary vascular tone, which may contribute to understanding sex differences in incidence, treatment response, and prognosis of pulmonary vascular disease.
尽管肺动脉高压在女性中的发病率较高，但在新生儿和成年人中，男性受试者的肺血管疾病严重程度和预后更差。关于肺动脉高压性别差异的研究主要集中在性激素的作用上。然而，关于调节肺血管功能的血管信号通路方面的性别差异的作用仍未完全了解。因此，我们研究了雄性和雌性猪在体内静息和运动状态下以及体外分离的小肺动脉中的肺血管功能，特别关注一氧化氮-环磷酸鸟苷-磷酸二酯酶5（NO-cGMP-PDE5）途径。雄性和雌性猪在静息和运动时的肺血流动力学几乎相同。此外，一氧化氮合酶抑制在雄性和雌性猪中导致相似程度的肺血管收缩。然而，一氧化氮合酶抑制使雄性猪肺小动脉中缓激肽诱导的血管舒张比雌性猪受到更大程度的抑制。磷酸二酯酶5抑制在静息时在雄性和雌性猪中导致相似程度的血管舒张，而在运动时雄性猪有产生更大效应的趋势。在小肺动脉中，磷酸二酯酶5抑制在两性中均未能增强缓激肽诱导的血管舒张。最后，在存在一氧化氮合酶抑制的情况下，磷酸二酯酶5抑制的肺血管舒张作用在雌性猪体内和体外均显著更大。总之，本研究证明了在肺血管张力调节方面存在显著的性别差异，这可能有助于理解肺血管疾病在发病率、治疗反应和预后方面的性别差异。
