Loss of cell polarity regulated by PTEN/Cdc42 enrolled in the process of Hepatopulmonary Syndrome
Loss of cell polarity regulated by PTEN/Cdc42 enrolled in the process of Hepatopulmonary Syndrome
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肝肺综合征过程中PTEN/Cdc42调控的细胞极性丧失
DOI：
10.1111/jcmm.14437
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发表时间：
2019-08-01
影响因子：
5.3
通讯作者：
Yi, Bin
中科院分区：
文献类型：
--
作者：
Gao, Jing;Yu, Hongfu;Yi, Bin
肝病综合征（HPS）发病机制的一个中心因素是肺血管重塑（PVR），其涉及肺微血管内皮细胞（PMVEC）增殖和迁移的失调。越来越多的证据表明，顶侧/基底侧极性在细胞增殖、迁移、粘附和分化中起着重要作用。在这项研究中，我们探讨了细胞极性是否参与和关键的实验性HPS大鼠胆总管结扎（CBDL）诱导。免疫荧光法检测CBDL大鼠肺组织和HPS血清刺激下PMVEC中细胞极性相关蛋白的表达。分别检测Cdc 42/PTEN活性、细胞增殖和迁移以及膜联蛋白A2（AnnexinA 2，AX 2）的表达。细胞极性相关蛋白在CBDL大鼠PMVEC中失去了其专门的管腔定位。细胞极性的丧失由Cdc 42的异常活性诱导，在用来自CBDL大鼠的血清处理后，PMVEC中p-PTEN和膜联蛋白A2之间的相互作用强烈增强了Cdc 42的异常活性。导致PMVEC过度增殖和高迁移能力。PTEN-Cdc 42活性在PMVEC中的下调恢复了细胞极性，从而降低了它们的迁移和增殖能力。我们的研究表明，细胞极性的丧失在HPS相关PVR的发病机制中起着关键作用，并可能成为潜在的有效治疗靶点。
One central factor in hepatopulmonary syndrome (HPS) pathogenesis is pulmonary vascular remodelling (PVR) which involves dysregulation of proliferation and migration in pulmonary microvascular endothelial cells (PMVECs). Growing evidence suggests that Apical/basolateral polarity plays an important role in cell proliferation, migration, adhesion and differentiation. In this study, we explored whether cell polarity is involved and critical in experimental HPS rats that are induced by common bile duct ligation (CBDL). Cell polarity related proteins were analysed in CBDL rats lung and PMVECs under the HPS serum stimulation by immunofluorescence assay. Cdc42/PTEN activity, cell proliferation and migration and Annexin A2 (AX2) in PMVECs were determined, respectively. Cell polarity related proteins, lost their specialized luminal localization in PMVECs of the CBDL rat. The loss of cell polarity was induced by abnormal activity of Cdc42, which was strongly enhanced by the interaction between p‐PTEN and Annexin A2 in PMVECs, after treatment with serum from CBDL rats. It led to over‐proliferation and high migration ability of PMVECs. Down‐regulation of PTEN‐Cdc42 activity in PMVECs restored cell polarity and thus reduced their ability of migration and proliferation. Our study suggested that the loss of cell polarity plays a critical role in the pathogenesis of HPS‐associated PVR and may become a potentially effective therapeutic target.