Dexmedetomidine Promotes Angiogenesis and Vasculogenic Mimicry in Human Hepatocellular Carcinoma through α 2-AR/HIF-1α/VEGFA Pathway.
- Author:
Tao FANG
1
,
2
;
Li LIN
2
;
Zhi Jian YE
2
;
Lian FANG
2
;
Shuai SHI
3
;
Ke Da YU
3
;
Hui Hui MIAO
4
;
Tian Zuo LI
4
Author Information
- Publication Type:Journal Article
- Keywords: Angiogenesis; Dexmedetomidine; HIF-1a; Hepatocellular carcinoma; VEGFA; Vascular mimicry; Yohimbine; α2-adrenergic receptor
- MeSH: Animals; Humans; Mice; Adrenergic alpha-2 Receptor Agonists/pharmacology*; Carcinoma, Hepatocellular; Cardiovascular Physiological Phenomena; Dexmedetomidine/pharmacology*; Hypoxia; Liver Neoplasms/drug therapy*; Oxygen; Tumor Microenvironment; Vascular Endothelial Growth Factor A/genetics*; Receptors, Adrenergic, alpha-2/metabolism*
- From: Biomedical and Environmental Sciences 2022;35(10):931-942
- CountryChina
- Language:English
-
Abstract:
OBJECTIVE:Dexmedetomidine (DEX), the most specific α 2-adrenergic receptor agonist widely used for its sedative and analgesic properties, has been reported to upregulate HIF-1α expression to protect hypoxic and ischemic tissues. However, it is largely unclear whether DEX can also upregulate Hypoxia-inducible factor-1 alpha (HIF-1α) expression and its downstream vascular endothelial growth factor-A (VEGFA) in cancer tissues with oxygen-deficient tumor microenvironment.
METHODS:We used SMMC-7721 cells, MHCC97-H cells, and a mouse model of orthotopic hepatic carcinoma to explore the effect of DEX on angiogenesis and vasculogenic mimicry (VM) and its mechanism. Under normoxic (20% O 2) and hypoxic (1% O 2) conditions, DEX was used to intervene cells, and yohimbine was used to rescue them.
RESULTS:The results showed that DEX promoted angiogenesis and VM in human liver cancer cells within a certain dose range, and the addition of yohimbine inhibited this effect. DEX could activate HIF-1α/VEGFA pathway, which was further verified by silencing HIF-1α. Consistently, in vivo results also showed that DEX can up-regulate HIF-1α/VEGFA expression, and enhance the number of VM channels and microvessel density (MVD).
CONCLUSION:We believe that HIF-1α/VEGFA might be an important signaling pathway by which DEX promotes angiogenesis and VM formation in human hepatocellular carcinoma, whereas α 2-adrenergic receptor mediation might be the critical mechanisms.
