Transcriptional Regulation of Thrombin-Induced Endothelial VEGF Induction and Proangiogenic Response.
Cells
; 10(4)2021 04 15.
Article
in English
| MEDLINE | ID: covidwho-1232577
ABSTRACT
Thrombin, the ligand of the protease-activated receptor 1 (PAR1), is a well-known stimulator of proangiogenic responses in vascular endothelial cells (ECs), which are mediated through the induction of vascular endothelial growth factor (VEGF). However, the transcriptional events underlying this thrombin-induced VEGF induction and angiogenic response are less well understood at present. As reported here, we conducted detailed promotor activation and signal transduction pathway studies in human microvascular ECs, to decipher the transcription factors and the intracellular signaling events underlying the thrombin and PAR-1-induced endothelial VEGF induction. We found that c-FOS is a key transcription factor controlling thrombin-induced EC VEGF synthesis and angiogenesis. Upon the binding and internalization of its G-protein-coupled PAR-1 receptor, thrombin triggers ERK1/2 signaling and activation of the nuclear AP-1/c-FOS transcription factor complex, which then leads to VEGF transcription, extracellular secretion, and concomitant proangiogenic responses of ECs. In conclusion, exposure of human microvascular ECs to thrombin triggers signaling through the PAR-1-ERK1/2-AP-1/c-FOS axis to control VEGF gene transcription and VEGF-induced angiogenesis. These observations offer a greater understanding of endothelial responses to thromboinflammation, which may help to interpret the results of clinical trials tackling the conditions associated with endothelial injury and thrombosis.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Transcription, Genetic
/
Thrombin
/
Gene Expression Regulation
/
Neovascularization, Physiologic
/
Vascular Endothelial Growth Factor A
Type of study:
Observational study
/
Prognostic study
Limits:
Humans
Language:
English
Year:
2021
Document Type:
Article
Affiliation country:
Cells10040910
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