title: The proangiogenic effect of iroquois homeobox transcription factor Irx3 in human microvascular endothelial cells.
abstract: Angiogenesis is a dynamic process required for embryonic development. However, postnatal vascular growth is characteristic of multiple disease states. Despite insights into the multistep process in which adhesion molecules, extracellular matrix proteins, growth factors, and their receptors work in concert to form new vessels from the preexisting vasculature, there remains a lack of insight of the nuclear transcriptional mechanisms that occur within endothelial cells (ECs) in response to VEGF. Iroquois homeobox gene 3 (Irx3) is a transcription factor of the Iroquois family of homeobox genes. Irx homeodomain transcription factors are involved in the patterning and development of several tissues. Irx3 is known for its role during embryogenesis in multiple organisms. However, the expression and function of Irx3 in human postnatal vasculature remains to be investigated. Here we show that Irx3 is expressed in human microvascular endothelial cells, and expression is elevated by VEGF stimulation. Genetic Irx3 gain and loss of function studies in human microvascular endothelial cells resulted in the modulation of EC migration during wound healing, chemotaxis and invasion, and tubulogenesis. Additionally, we observed increased delta-like ligand 4 (Dll4) expression, which suggests an increase in EC tip cell population. Finally, siRNA screening studies revealed that transient knockdown of Hey1, a downstream Notch signaling mediator, resulted in increased Irx3 expression in response to VEGF treatment. Strategies to pharmacologically regulate Irx3 function in adult endothelial cells may provide new therapies for angiogenesis.
authors.affiliation: From the Cardiovascular Research Institute and.
authors.forename: Kisha
authors.initials: K
authors.lastname: Scarlett
authors.affiliation: From the Cardiovascular Research Institute and.
authors.forename: Vaishnavi
authors.initials: V
authors.lastname: Pattabiraman
authors.affiliation: the Cancer Center for Therapeutic Development, Clark Atlanta University, Atlanta, Georgia 30314.
authors.forename: Petrina
authors.initials: P
authors.lastname: Barnett
authors.affiliation: From the Cardiovascular Research Institute and Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia 30310 and.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: From the Cardiovascular Research Institute and Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia 30310 and landerson@msm.edu.
authors.forename: Leonard M
authors.initials: LM
authors.lastname: Anderson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D009389:Neovascularization, Pathologic / Q000235:genetics*; D051880:Receptors, Notch / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C501598:IRX3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A
keywords: Angiogenesis; Cell Migration; Endothelial Cell; Irx3; Notch Pathway; Transcription Factor; VEGF