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Caffeine promotes angiogenesis through modulating endothelial mitochondrial dynamics

Li-tao Wang1,2, Peng-cheng He1,2, An-qi Li3,4,5, Kai-xiang Cao3,4,5, Jing-wei Yan3,4,5, Shuai Guo3,4,5, Lei Jiang1,2, Lin Yao6, Xiao-yan Dai7, Du Feng3,4,5, Yi-ming Xu3,4,5, Ning Tan1,2
1 uangdong Provincial People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510100, China
2 epartment of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510100, China
3 ingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 511436, China
4 tate Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou 511436, China
5 chool of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
6 chool of Pharmaceutical Sciences, South China Research Center for Acupuncture and Moxibustion, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
7 uangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
Correspondence to: Yi-ming Xu: xuyiming0807@gmail.com, Ning Tan: gdtanning@126.com,
DOI: 10.1038/s41401-021-00623-6
Received: 28 October 2020
Accepted: 7 February 2021
Advance online: 4 March 2021

Abstract

Caffeine induces multiple vascular effects. In this study we investigated the angiogenic effect of physiological concentrations of caffeine with focus on endothelial cell behaviors (migration and proliferation) during angiogenesis and its mitochondrial and bioenergetic mechanisms. We showed that caffeine (10–50 μM) significantly enhanced angiogenesis in vitro, evidenced by concentration-dependent increases in tube formation, and migration of human umbilical vein endothelial cells (HUVECs) without affecting cell proliferation. Caffeine (50 μM) enhanced endothelial migration via activation of cAMP/PKA/AMPK signaling pathway, which was mimicked by cAMP analog 8-Br-cAMP, and blocked by PKA inhibitor H89, adenylate cyclase inhibitor SQ22536 or AMPK inhibitor compound C. Furthermore, caffeine (50 μM) induced significant mitochondrial shortening through the increased phosphorylation of mitochondrial fission protein dynamin-related protein 1 (Drp1) in HUVECs, which increased its activity to regulate mitochondrial fission. Pharmacological blockade of Drp1 by Mdivi-1 (10 μM) or disturbance of mitochondrial fission by Drp1 silencing markedly suppressed caffeine-induced lamellipodia formation and endothelial cell migration. Moreover, we showed that caffeine-induced mitochondrial fission led to accumulation of more mitochondria in lamellipodia regions and augmentation of mitochondrial energetics, both of which were necessary for cell migration. In a mouse model of hindlimb ischemia, administration of caffeine (0.05% in 200 mL drinking water daily, for 14 days) significantly promoted angiogenesis and perfusion as well as activation of endothelial AMPK signaling in the ischemic hindlimb. Taken together, caffeine induces mitochondrial fission through cAMP/PKA/AMPK signaling pathway. Mitochondrial fission is an integral process in caffeine-induced endothelial cell migration by altering mitochondrial distribution and energetics.
Keywords: caffeine; angiogenesis; endothelial cells; migration; mitochondrial dynamics; cAMP/PKA/AMPK signaling; mouse model of hindlimb ischemia

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