Date of Award

Spring 12-12-2022

Degree Type


Degree Name

Doctor of Philosophy (PhD)



First Advisor

Zhonglin Xie


Autophagy is an intracellular degradation system that delivers cytoplasmic components to the lysosome for degradation. Autophagy is essential for cellular homeostasis and provides a mechanism to adapt to metabolic and stress cues. Endothelial autophagy regulates the response of ECs to a variety of stress factors related to EC homeostasis and plasticity. However, the precise role of autophagy in angiogenesis requires more detailed research. Although autophagy-related 7 (ATG7) is essential for classical degradative autophagy and cell cycle regulation, whether and how ATG7 influences endothelial cell (EC) function and regulates post-ischemic angiogenesis remain unknown. Endothelial dysfunction is a potential contributor to the pathogenesis of diabetic cardiovascular complications. However, little is known about disruptions of endothelial autophagy contributing to diabetes-induced endothelial dysfunction. This dissertation aims to address how ATG7 influences endothelial cell (EC) function and regulates post-ischemic angiogenesis, and to determine the role of autophagy in the development of endothelial dysfunction.

EC-specific deletion of Atg7 significantly impaired angiogenesis, delayed the recovery of blood flow reperfusion, and displayed reduction in hypoxia inducible factor 1 subunit alpha (HIF1A) expression. Mechanistically, lack of ATG7 in the cytoplasm disrupted the association between ATG7 and transcription factor ZNF148/ZBP-89 that is required for STAT1 (signal transducer and activator of transcription1) constitutive expression, increased the binding between ZNF148/ZBP-89 and importin-β1 (KPNB1), which promoted ZNF148/ZBP-89 nuclear translocation, and increased STAT1 expression. STAT1 bond to HIF1A promotor and suppressed HIF1A mRNA expression, thereby preventing ischemia-induced angiogenesis. These results demonstrate that ATG7 deficiency is a novel suppressor of ischemia-induced angiogenesis.

In addition, streptozotocin (STZ)-induced type 1 diabetes inhibits autophagic flux and reduced protein levels of autophagy gene related protein, including ULK1, ATG7, ATG5, and Beclin1, which was accompanied by an impairment of acetylcholine-induced relaxation of isolated mouse aortas. Inhibition of endothelial autophagy by the deletion of endothelial ULK1 exacerbated diabetes-induced endothelial dysfunction, reactive oxygen species (ROS) overproduction and impeded endothelial nitric oxide synthase (eNOS) phosphorylation. Mechanistically, suppression of autophagy by diabetes aggravated ROS overproduction. Downregulation of ULK1 reduced eNOS phosphorylation. Thus, promoting autophagy activity may be a potential strategy to prevent endothelial dysfunction in diabetes.


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