Autophagy promotes angiogenesis via AMPK/Akt/mTOR signaling during the recovery of heat-denatured endothelial cells

Pengfei Liang,Xianzhong Xiao,Zhenguo Liu,Xiaoyuan Huang,Bimei Jiang,Minghua Zhang,Yuanbin Li,Pihong Zhang

doi:10.1038/s41419-018-1194-5

Abstract

Our previous study demonstrated that angiogenesis increased during the recovery of heat-denatured endothelial cells. However, the mechanism is still unclear. This study aimed to investigate the relation of autophagy and angiogenesis during the recovery of heat-denatured endothelial cells. A rat deep partial-thickness burn model and heat-denatured human umbilical vein endothelial cells (HUVECs) model (52 °C for 35 s) were used. Autophagy increased significantly in the dermis and HUVECs in a time-dependent manner after heat denaturation and recovery for 2–5 days. Rapamycin-mediated autophagy enhanced the pro-angiogenic effect, evidenced by increased proliferation and migration of HUVECs, and formation of tube-like structures. Autophagy inhibition by 3-Methyladenine (3-MA) abolished the angiogenesis in heat-denatured HUVECs after recovery for 3–5 days. Moreover, heat denaturation augmented the phosphorylation of AMP-activated protein kinase (AMPK) but reduced the phosphorylation of Akt and mTOR in HUVECs. Furthermore, autophagy inhibition by antioxidant NAC, compound C or AMPK siRNA impaired cell proliferation, migration and tube formation heat-denatured HUVECs. At last, the in vivo experiments also showed that inhibition of autophagy by bafilomycin A1 could suppress angiogenesis and recovery of heat-denatured dermis.Taken together, we firstly revealed that autophagy promotes angiogenesis via AMPK/Akt/mTOR signaling during the recovery of heat-denatured endothelial cells and may provide a potential therapeutic target for the recovery of heat-denatured dermis.

Highlights

Denatured dermis was firstly put forward by Huang et al in 20011
We found that heat denaturation could activate autophagy in human umbilical vein endothelial cells (HUVECs) in vitro and in heat-denatured dermis in vivo
We demonstrated cellular autophagy was augmented during the recovery of heatdenatured dermis and heat-denatured HUVECs, which is dependent on intracellular reactive oxygen species (ROS) production

Summary

Introduction

Denatured dermis was firstly put forward by Huang et al in 20011. In deep partial burn wound, denatured dermis appears cell metabolism disorder, function impairment and markedly morphological changes. Denatured dermis has the ability to restore normal morphology and function after improving the Angiogenesis, a crucial process for wound healing, is involved in several sequential phases, in which sprout formation is initiated after the degradation of surrounding basement membrane by proteolytic enzymes secreted from endothelial cells, followed by endothelial cell proliferation and migration. Liang et al Cell Death and Disease (2018)9:1152 increased during the recovery of heat-denatured HUVECs as evidenced by the increase in endothelial cell proliferation, migration and tube formation[7]. The mechanisms of pro-angiogenesis during the recovery of heat-denatured HUVECs have not been explored clearly

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