NOR-1 is involved in VEGF-induced endothelial cell growth.
Neuron-derived orphan receptor-1 (NOR-1) is a transcription factor over-expressed in human atherosclerotic plaques that is involved in vascular smooth muscle cell proliferation. The aim of this study was to analyze whether NOR-1 plays a role in vascular endothelial growth factor (VEGF) induced endothelial cell growth. VEGF induced an early and transient up-regulation of NOR-1 in human umbilical vein endothelial cells (HUVEC). NOR-1 up-regulation by VEGF is processed through VEGF receptor-2 (VEGFR-2) and involves different signaling pathways including increase in cytosolic Ca(2+), activation of protein kinase C and mitogen-activated protein kinase (MAPK) pathways (both extracellular-signaling regulated kinase [ERK] and p38 MAPK). VEGF induced CREB activation (phosphorylation in Ser(133)). In transfection assays, a dominant-negative of CREB inhibited NOR-1 promoter activity, while mutation of the three CRE sites in the NOR-1 promoter abolished VEGF-induced NOR-1 promoter activity. Antisense oligonucleotides against NOR-1 inhibited VEGF-induced endothelial cell growth (reduced DNA synthesis, and inhibited cell cycle progression and endothelial cell wound repair after mechanical injury). These results indicate that NOR-1 could be a key transcription factor regulating endothelial cell growth induced by VEGF.
Rius
Jordi
J
Centro de Investigación Cardiovascular, CSIC/ICCC, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret # 167, Barcelona 8025, Spain.
Martínez-González
José
J
Crespo
Javier
J
Badimon
Lina
L
D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics*; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D004268:DNA-Binding Proteins; C490412:NR4A3 protein, human; D009419:Nerve Tissue Proteins; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D042461:Vascular Endothelial Growth Factor A; D012313:RNA