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Identification of specifically activated angiogenic molecules in HMGB-1-induced angiogenesis

ABSTRACT: High-mobility group box-1 (HMGB-1), a nonhistone chromosomal protein, is expressed in almost all types of cells with nucleus, and dysregulation of its expression correlates with pathological conditions such as inflammatory diseases, ischemia and cancers. Some of these conditions accompany abnormal angiogenesis induced by HMGB-1 mediated activation of downstream signaling pathways. So far, the underlying mechanism by which HMGB-1 induces angiogenesis remains largely unknown. In this study, we performed time-dependent gene expression microarray in endothelial cells (ECs) after HMGB-1 or VEGF treatment. By pathway analysis using each gene set up-regulated by HMGB-1 or VEGF, we found that most of HMGB-1 induced angiogenic pathways were also commonly activated by VEGF, while activation time and gene sets belonging to the pathways were different. In addition, HMGB-1 up-regulated some VEGFR signaling related conventional angiogenic factors including EGR1 and importantly, novel angiogenic factors such as ABL2, CEACAM1, KIT and VIPR1 which have been reported to independently promote angiogenesis in physiological and pathological conditions. Our gene expression profiling suggests that HMGB-1 is capable of independently inducing angiogenesis through activation of HMGB-1 specific angiogenic factors and also functions as an accelerator for VEGF mediated conventional angiogenesis according to physiological and pathological condition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100404 | GEO | 2017/12/29

SECONDARY ACCESSION(S): PRJNA391577

REPOSITORIES: GEO

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Project description:The small GTPase RhoA regulates a variety of cellular processes, including cell motility, proliferation, survival and permeability. In addition, there are reports suggesting that the RhoA-ROCK axis plays a role in VEGF-mediated angiogenesis, whereas other work has shown opposite effects. To elucidate this conflicting data, we examined HUVEC and HCAEC after stable overexpression (lentiviral transduction) of constitutively active (G14V/Q63L), dominant-negative (T19N), or wild-type RhoA using a variety of in vitro angiogenesis assays (proliferation, migration, tube formation, angiogenic sprouting, endothelial cell viability) and a HUVEC xenograft assay in immune incompetent NSGTM mice in vivo. We observed that expression of active as well as wild-type RhoA but not expression of dominant-negative RhoA significantly increased endothelial cell death as well as inhibited endothelial cell proliferation, migration, tube formation and angiogenic sprouting of endothelial cells in vitro and reduced HUVEC-related angiogenesis in vivo. Inhibition of RhoA by C3 transferase antagonized inhibitory RhoA effects and strongly enhanced VEGF-induced angiogenic sprouting in control-treated cells. In contrast, inhibition of RhoA effectors ROCK1/2 and LIMK1/2 had no significant effect on RhoA-related effects, but again increased angiogenic sprouting and migration of control-treated cells. In line with these data, VEGF did not activate RhoA in HUVEC as measured by a FRET-based biosensor. Furthermore, global transcriptome and subsequent bioinformatic gene ontology (GO) enrichment analyses revealed that constitutively active RhoA induces a differentially expressed gene pattern that is enriched for GO biological process terms such as mitotic nuclear division, cell proliferation, cell motility and cell adhesion and includes a significant decrease in VEGFR-2 and NOS3 expression. Thus, our data demonstrate that increased RhoA activity has the potential to trigger endothelial dysfunction and anti-angiogenic effects independently of its well-characterized downstream effectors ROCK and LIMK.

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Identification of specifically activated angiogenic molecules in HMGB-1-induced angiogenesis

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