The Circadian System Is Essential for the Crosstalk of VEGF-Notch-mediated Endothelial Angiogenesis in Ischemic Stroke

 Yuxing Zhang1,2,3 · Xin Zhao3  · Chun Guo1  · Ying Zhang1,3 · Fukang Zeng1,2,3 · Qian Yin3  · Zhong Li1  · Le Shao3,4 · Desheng Zhou1  · Lijuan Liu1
1 Department of Neurology, The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, China 
2 Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Changsha 410208, China 
3 Hunan University of Chinese Medicine, Changsha 410006, China 
4 Laboratory of Prevention and Transformation of Major Diseases in Internal Medicine of Traditional Chinese Medicine, Changsha 410007, China


Ischemic stroke is a major public health problem worldwide. Although the circadian clock is involved in the process of ischemic stroke, the exact mechanism of the circadian clock in regulating angiogenesis after cerebral infarction remains unclear. In the present study, we determined that environmental circadian disruption (ECD) increased the stroke severity and impaired angiogenesis in the rat middle cerebral artery occlusion model, by measuring the infarct volume, neurological tests, and angiogenesis-related protein. We further report that Bmal1 plays an irreplaceable role in angiogenesis. Overexpression of Bmal1 promoted tube-forming, migration, and wound healing, and upregulated the vascular endothelial growth factor (VEGF) and Notch pathway protein levels. This promoting effect was reversed by the Notch pathway inhibitor DAPT, according to the results of angiogenesis capacity and VEGF pathway protein level. In conclusion, our study reveals the intervention of ECD in angiogenesis in ischemic stroke and further identifies the exact mechanism by which Bmal1 regulates angiogenesis through the VEGF-Notch1 pathway.

Circadian clock; Ischemic stroke; Angiogenesis; VEGF; Notch pathway