Involvement of BIG1 and BIG2 in regulating VEGF expression and angiogenesis

Abstract

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.‐L, Wang, Y.‐T., Wang, Y.‐S., Wu, C.‐Y., Li, C.‐C. Involvement of BIG1 and BIG2 in regulating VEGF expression and angiogenesis. FASEB J. 33, 9959–9973 (2019). http://www.fasebj.org

Cytotoxic Evaluation and Anti-Angiogenic Effects of Two Furano-Sesquiterpenoids from Commiphora myrrh Resin

“…Various studies have reported the anti-angiogenic profile of myrrh within in vitro or in vivo systems [54][55][56][57]. During zebrafish embryonic development, the inter-somatic blood vessels and sub-intestinal vein are considered angiogenic blood vessels (which emerge from pre-existing blood vessels) and hence provide a quantitative tool to measure the angiogenic activity of natural products or synthetic compounds in live zebrafish embryos [58][59][60][61]. CM1 impeded the development of the sub-intestinal vein in the treated embryos.…”

A Reassessment of Copy Number Variations in Congenital Heart Defects: Picturing the Whole Genome

“…These genes are present in 18 different CNV-US, of which three occurred de novo (containing AUTS2 , CHD8 and TRIM28 ). These genes and their potential link to heart development and/or CHD (including the most relevant results from an additional Pubmed search looking for associations of these genes with (congenital) heart disease and/or heart development) are represented in Supplementary Table S5 [ 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ].…”

Differential protein expression in endothelial cells exposed to serum from patients with acute graft‐vs‐host disease, depending on steroid response

“… 28 There is evidence indicating that a depletion of proteins BIG1 and BIG2 inhibits angiogenesis in HUVECs. 55 According to these results, BIG1 might act by stimulating the formation of new blood vessels by inducing EC proliferation and migration. However, other proteins identified in this study (RICTR) related to proliferation are downregulated in steroid‐refractory conditions, and differences in angiogenesis with respect to the steroid‐sensitive condition should be confirmed.…”

“…However, other proteins identified in this study (RICTR) related to proliferation are downregulated in steroid‐refractory conditions, and differences in angiogenesis with respect to the steroid‐sensitive condition should be confirmed. Protein BIG1 is also related to DNA repair and participates in protein synthesis and vesicular transport within the cell 55 . On the contrary, another protein (CETN2) is also involved in DNA repair 56 and genome stability, 57 as well as actin binding and cytoskeleton organization.…”