期刊
FASEB JOURNAL
卷 33, 期 9, 页码 9959-9973出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201900342RR
关键词
ARFGEF; ARF1; small GTPase; endothelial cell; cell migration
资金
- Laboratory Animal Center, Medical College, National Cheng Kung University
- Ministry of Science and Technology in Taiwan (MOST) [MOST 104-2311-B-006-005-MY3, MOST 107-2311-B-006-001, MOST 104-2320-B-006-032-MY3, MOST 107-2320-B-006-041]
- Integrative Evolutionary Galliforms Genomics Research (iEGG) from The Feature Area Research Center Program by Ministry of Education (MOE) in Taiwan [MOE-107-S-0023-F]
- Animal Biotechnology Center from The Feature Area Research Center Program by Ministry of Education (MOE) in Taiwan [MOE-107-S-0023-F]
VEGF stimulates the formation of new blood vessels by inducing endothelial cell (EC) proliferation and migration. Brefeldin A (BFA)-inhibited guanine nucleotide-exchange protein (BIG)1 and 2 accelerate the replacement of bound GDP with GTP to activate ADP-ribosylation factor (Arf)1, which regulates vesicular transport between the Golgi and plasma membrane. Although it has been reported that treating cells with BFA interferes with Arf1 activation to inhibit VEGF secretion, the role of BIG1 and BIG2 in VEGF trafficking and expression, EC migration and proliferation, and vascular development remains unknown. Here, we found that inactivation of Arf1 reduced VEGF secretion but did not affect the levels of VEGF protein. Interestingly, however, BIG1 and BIG2 knockdown significantly decreased the levels of VEGF mRNA and protein in glioblastoma U251 cells and HUVECs. Furthermore, depletion of BIG1 and BIG2 inhibited HUVEC angiogenesis by diminishing cell migration. Angioblast migration and intersegmental vessel sprouting were also impaired when the BIG2 homolog, Arf guanine nucleotide exchange factor (arfgef)2, was knocked down in zebrafish with endothelial expression of green fluorescent protein (GFP). Depletion of arfgef2 by clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) also caused defects in vascular development of zebrafish embryos. Taken together, these data reveal that BIG1 and BIG2 participate in endothelial cell angiogenesis.-Lu, F.-I., Wang, Y.-T., Wang, Y.-S., Wu, C.-Y., Li, C.-C. Involvement of BIG1 and BIG2 in regulating VEGF expression and angiogenesis.
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