Awad Keytam S, West James D, de Jesus Perez Vinicio, MacLean Margaret
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Pulm Circ. 2016 Sep;6(3):285-94. doi: 10.1086/688034.
The proliferative endothelial and smooth muscle cell phenotype, inflammation, and pulmonary vascular remodeling are prominent features of pulmonary arterial hypertension (PAH). Mutations in bone morphogenetic protein type 2 receptor (BMPR2) have been identified as the most common genetic cause of PAH and females with BMPR2 mutations are 2.5 times as likely to develop heritable forms of PAH than males. Higher levels of estrogen have also been observed in males with PAH, implicating sex hormones in PAH pathogenesis. Recently, the estrogen metabolite 16α-OHE1 (hydroxyestrone) was implicated in the regulation of miR29, a microRNA involved in modulating energy metabolism. In females, decreased miR96 enhances serotonin's effect by upregulating the 5-hydroxytryptamine 1B (5HT1B) receptor. Because PAH is characterized as a quasi-malignant disease, likely due to BMPR2 loss of function, altered signaling pathways that sustain this cancer-like phenotype are being explored. Extracellular signal-regulated kinases 1 and 2 and p38 mitogen-activated protein kinases (MAPKs) play a critical role in proliferation and cell motility, and dysregulated MAPK signaling is observed in various experimental models of PAH. Wnt signaling pathways preserve pulmonary vascular homeostasis, and dysregulation of this pathway could contribute to limited vascular regeneration in response to injury. In this review, we take a closer look at sex, sex hormones, and the interplay between sex hormones and microRNA regulation. We also focus on MAPK and Wnt signaling pathways in the emergence of a proproliferative, antiapoptotic endothelial phenotype, which then orchestrates an angioproliferative process of vascular remodeling, with the hope of developing novel therapies that could reverse the phenotype.
增殖性内皮细胞和平滑肌细胞表型、炎症以及肺血管重塑是肺动脉高压（PAH）的显著特征。骨形态发生蛋白2型受体（BMPR2）突变已被确定为PAH最常见的遗传病因，携带BMPR2突变的女性患遗传性PAH的可能性是男性的2.5倍。在患有PAH的男性中也观察到较高水平的雌激素，这表明性激素参与了PAH的发病机制。最近，雌激素代谢产物16α - OHE1（羟雌酮）被认为参与了miR29的调节，miR29是一种参与调节能量代谢的微小RNA。在女性中，miR96水平降低通过上调5 - 羟色胺1B（5HT1B）受体增强了血清素的作用。由于PAH被认为是一种准恶性疾病，可能是由于BMPR2功能丧失，因此正在探索维持这种癌症样表型的信号通路改变。细胞外信号调节激酶1和2以及p38丝裂原活化蛋白激酶（MAPK）在细胞增殖和运动中起关键作用，并且在PAH的各种实验模型中观察到MAPK信号失调。Wnt信号通路维持肺血管稳态，该通路失调可能导致损伤后血管再生受限。在这篇综述中，我们更深入地探讨性别、性激素以及性激素与微小RNA调节之间的相互作用。我们还关注MAPK和Wnt信号通路在促增殖、抗凋亡内皮细胞表型出现中的作用，这种表型随后协调血管重塑的血管增殖过程，希望开发出能够逆转这种表型的新疗法。
