Bone morphogenic protein-2 regulates the myogenic differentiation of PMVECs in CBDL rat serum-induced pulmonary microvascular remodeling
Bone morphogenic protein-2 regulates the myogenic differentiation of PMVECs in CBDL rat serum-induced pulmonary microvascular remodeling
复制标题
骨形态发生蛋白-2 在 CBDL 大鼠血清诱导的肺微血管重塑中调节 PMVEC 的肌源性分化。
DOI：
10.1016/j.yexcr.2015.05.025
复制
发表时间：
2015-08-01
影响因子：
3.7
通讯作者：
Yi, Bin
中科院分区：
文献类型：
--
作者：
Liu, Chang;Chen, Lin;Yi, Bin
肝肺综合征（HPS）的特点是由肺内血管舒张（IPVD）引起的动脉氧合缺陷，增加了发病率和死亡率。我们前期研究发现肺微血管内皮细胞（pulmonary microvascular endothelial cells, PMVECs）的增殖和成肌分化在IPVD的发生发展中起关键作用。然而，IPVD与PMVECs肌源性分化之间关系的分子机制尚不清楚。此外，研究表明，骨形态发生蛋白-2 （bone morphogenic protein-2, BMP2）可通过控制蛋白表达来调节细胞分化，包括心肌细胞分化、神经元分化和成牙细胞分化。在本研究中，我们观察到胆总管结扎(CBDL)-大鼠血清诱导PMVECs中几种肌原性蛋白（sm - α -actin, calponin, SM-MHC）的表达上调，并增强BMP2 mRNA和蛋白的表达水平。我们还观察到，暴露于cbdl大鼠血清后，PMVECs中Smad1/5的表达水平和磷酸化Smad1/5的激活水平均显著升高，同时伴有Smurf1的下调。用Noggin阻断BMP2/Smad信号通路抑制PMVECs的肌源性分化，这一过程与cbdl大鼠血清暴露下sm - α -肌动蛋白和钙钙蛋白的相对低表达水平有关，尽管SM-MHC的表达不受影响。这些发现表明BMP2/Smad信号通路参与了pmvec的肌源性分化。总之，我们的数据强调了BMP2通过激活Smad1和Smad5以及下调Smurfl在cbdl大鼠血清诱导的PMVECs肌源性分化中的关键作用，这可能代表了hps诱导的肺血管重构的潜在治疗方法。(C) 2015爱思唯尔公司版权所有。
Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect induced by intrapulmonary vasodilation (IPVD) that increases morbidity and mortality. In our previous study, it was determined that both the proliferation and the myogenic differentiation of pulmonary microvascular endothelial cells (PMVECs) play a key role in the development of IPVD. However, the molecular mechanism underlying the relationship between IPVD and the myogenic differentiation of PMVECs remains unknown. Additionally, it has been shown that bone morphogenic protein-2 (BMP2), via the control of protein expression, may regulate cell differentiation including cardiomyocyte differentiation, neuronal differentiation and odontoblastic differentiation. In this study, we observed that common bile duct ligation (CBDL)-rat serum induced the upregulation of the expression of several myogenic proteins (SM-alpha-actin, calponin, SM-MHC) and enhanced the expression levels of BMP2 mRNA and protein in PMVECs. We also observed that both the expression levels of Smad1/5 and the activation of phosphorylated Smad1/5 were significantly elevated in PMVECs following exposure to CBDL-rat serum, which was accompanied by the down-regulation of Smurf1. The blockage of the BMP2/Smad signaling pathway with Noggin inhibited the myogenic differentiation of PMVECs, a process that was associated with relatively low expression levels of both SM-alpha-actin and calponin in the setting of CBDL-rat serum exposure, although SM-MHC expression was not affected. These findings suggested that the BMP2/Smad signaling pathway is involved in the myogenic differentiation of the PMVECs. In conclusion, our data highlight the pivotal role of BMP2 in the CBDL-rat serum-induced myogenic differentiation of PMVECs via the activation of both Smad1 and Smad5 and the down-regulation of Smurfl, which may represent a potential therapy for HPS-induced pulmonary vascular remodeling. (C) 2015 Elsevier Inc. All rights reserved.