title: The VEGF-regulated transcription factor HLX controls the expression of guidance cues and negatively regulates sprouting of endothelial cells.
abstract: The HLX gene encoding a diverged homeobox transcription factor has been found to be up-regulated by vascular endothelial growth factor-A (VEGF-A) in endothelial cells. We have now investigated the gene repertoire induced by HLX and its potential biologic function. HLX strongly increased the transcripts for several repulsive cell-guidance proteins including UNC5B, plexin-A1, and semaphorin-3G. In addition, genes for transcriptional repressors such as HES-1 were up-regulated. In line with these findings, adenoviral overexpression of HLX inhibited endothelial cell migration, sprouting, and vessel formation in vitro and in vivo, whereas proliferation was unaffected. This inhibition of sprouting was caused to a significant part by HLX-mediated up-regulation of UNC5B as shown by short hairpin RNA (shRNA)-mediated down-modulation of the respective mRNA. VEGF-A stimulation of endothelial cells induced elevated levels of HLX over longer time periods resulting in especially high up-regulation of UNC5B mRNA as well as an increase in cells displaying UNC5B at their surface. However, induction of HLX was strongly reduced and UNC5B up-regulation completely abrogated when cells were exposed to hypoxic conditions. These data suggest that HLX may function to balance attractive with repulsive vessel guidance by up-regulating UNC5B and to down-modulate sprouting under normoxic conditions.
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Testori
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schweighofer
authors.forename: Iris
authors.initials: I
authors.lastname: Helfrich
authors.forename: Caterina
authors.initials: C
authors.lastname: Sturtzel
authors.forename: Karoline
authors.initials: K
authors.lastname: Lipnik
authors.forename: Sabine
authors.initials: S
authors.lastname: Gesierich
authors.forename: Patrick
authors.initials: P
authors.lastname: Nasarre
authors.forename: Renate
authors.initials: R
authors.lastname: Hofer-Warbinek
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.forename: Erhard
authors.initials: E
authors.lastname: Hofer
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000254:growth & development; D015687:Cell Hypoxia / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D018919:Neovascularization, Physiologic; D000075386:Netrin Receptors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D018874:Spheroids, Cellular / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C084058:HLX protein, human; D018398:Homeodomain Proteins; D000075386:Netrin Receptors; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D014157:Transcription Factors; C532445:UNC5B protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A