Loss of cell polarity regulated by PTEN/Cdc42 enrolled in the process of Hepatopulmonary Syndrome.

Jing Gao,Xiaobo Wang,Xuehong Bai,Zhiyong Hu,Karine Belguise,Hongfu Yu,Bin Yi,Lin Chen,Chang Liu,Kaizhi Lu

doi:10.1111/jcmm.14437

Abstract

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.

Highlights

There are 100 million hepatitis B virus carriers in China
In our previ‐ ous studies, we established the role of cell proliferation, migration and phenotype differentiation in Pulmonary vascular remodelling (PVR) associated with Hepatopulmonary Syndrome (HPS).[4-7]
Our previous studies established the role of cell proliferation, migra‐ tion and phenotype differentiation in PVR associated with HPS.[4-7]

Summary

| INTRODUCTION

There are 100 million hepatitis B virus carriers in China. Approximately 20%–40% of them developed hepatitis‐cirrhosis and 20%–30% of these hepatitis‐cirrhosis patients end up with Hepatopulmonary Syndrome (HPS)[1,2] which significantly increases mortality. In our previ‐ ous studies, we established the role of cell proliferation, migration and phenotype differentiation in PVR associated with HPS.[4-7]. It is important to characterize specific molecules that might control the multiple cellular activities required for cell polarization and to elucidate their regulatory mechanism in the process of PVR in HPS. We demonstrated that the loss of apical/basolateral polarity in PMVECs occurred in the process of PVR associated with HPS. This cell polarity loss was mediated by the enhanced PTEN‐Annexin A2(AX2)‐Cdc[42] signalling pathway, and the down‐regulation of this signalling pathway can restore cell polarity and reduce the abnormal migration and proliferation ability of PMVECs in response to com‐ mon bile duct ligation (CDBL) rat serum

| MATERIALS AND METHODS

Findings

| DISCUSSION