Endothelial Cdc42 deficiency impairs endothelial regeneration and vascular repair after inflammatory vascular injury

Jiawen Lv,Lin Zhang,Yinghua Chen,Mengying Xu,Shaoxi Cai,Yi Zheng,Fukun Guo,Junchao Zeng,Yuanxiong Cheng,Guodong Hu,Yiran Li

doi:10.1186/s12931-018-0729-8

Abstract

BackgroundEndothelial cell (EC) regeneration is essential for inflammation resolution and vascular integrity recovery after inflammatory vascular injury. Cdc42 is a central regulator of cell survival and vessel formation in EC development. However, it is unknown that whether Cdc42 could be a regulating role of EC repair following the inflammatory injury in the lung. The study sought to test the hypothesis that Cdc42 is required for endothelial regeneration and vascular integrity recovery after LPS-induced inflammatory injury.Methods and resultsThe role of Cdc42 for the regulation of pulmonary vascular endothelial repair was tested in vitro and in vivo. In LPS-induced acute lung injury (ALI) mouse models, knockout of the Cdc42 gene in ECs increased inflammatory cell infiltration and pulmonary vascular leakage and inhibited vascular EC proliferation, which eventually resulted in more severe inflammatory lung injury. In addition, siRNA-mediated knockdown of Cdc42 protein on ECs disrupted cell proliferation and migration and tube formation, which are necessary processes for recovery after inflammatory vascular injury, resulting in inflammatory vascular injury recovery defects.ConclusionWe found that Cdc42 deficiency impairs EC function and regeneration, which are crucial in the post-inflammatory vascular injury repair process. These findings indicate that Cdc42 is a potential target for novel treatments designed to facilitate endothelial regeneration and vascular repair in inflammatory pulmonary vascular diseases, such as ALI/ARDS.

Highlights

Endothelial cell (EC) regeneration is essential for inflammation resolution and vascular integrity recovery after inflammatory vascular injury
These findings indicate that Cdc42 is a potential target for novel treatments designed to facilitate endothelial regeneration and vascular repair in inflammatory pulmonary vascular diseases, such as Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS)
We observed that the green fluorescence indicative of the presence of Cdc42 was absent in vascular endothelial cells in Cdc42-KO mice and was present in other tissues in the lungs of these mice, demonstrating that Cdc42 had been knocked out in pulmonary vascular ECs

Summary

Introduction

Endothelial cell (EC) regeneration is essential for inflammation resolution and vascular integrity recovery after inflammatory vascular injury. The vascular endothelium functions as a barrier that protects the vasculature from disruptive stimuli, Acute lung injury (ALI) and its most severe state, acute respiratory distress syndrome (ARDS), are critical clinical diseases with high annual mortality rates for which no specific pharmacologic therapies are available [8,9,10]. These diseases have multiple causes, including infection, toxin inhalation or physical injury. Studies elucidating the mechanisms underlying EC recovery and vascular repair after injury are urgently needed to develop novel methods for treating ALI/ARDS

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Results

Conclusion