title: Urokinase receptor associates with myocardin to control vascular smooth muscle cells phenotype in vascular disease.
abstract: OBJECTIVE
  The urokinase-type plasminogen activator (uPA) and its specific receptor (uPAR) are a potent multifunctional system involved in vascular remodeling. The goal of the study was to unravel the mechanisms of uPA/uPAR-directed vascular smooth muscle cell (VSMC) differentiation.
  
  
  RESULTS
  Using cultured human primary VSMCs, we identified a new molecular mechanism controlling phenotypic modulation in vitro and in vivo. We found that the urokinase-type plasminogen activator receptor (uPAR) acts together with the transcriptional coactivator myocardin to regulate the VSMC phenotype. uPAR, a glycosylphosphatidylinositol-anchored cell-surface receptor family member, undergoes ligand-induced internalization and nuclear transport in VSMCs. Platelet-derived growth factor receptor β and SUMOylated RanGAP1 mediate this trafficking. Nuclear uPAR associates with myocardin, which is then recruited from the promoters of serum response factor target genes and undergoes proteasomal degradation. This chain of events initiates the synthetic VSMC phenotype. Using mouse carotid artery ligation model, we show that this mechanism contributes to adverse vascular remodeling after injury in vivo. We then cultured cells on a microstructured biomaterial and found that substrate topography induced uPAR-mediated VSMC differentiation.
  
  
  CONCLUSIONS
  These findings reveal the transcriptional activity of uPAR, controlling the differentiation of VSMCs in a vascular disease model. They also suggest a new role for uPAR as a therapeutic target and as a marker for VSMC phenotyping on prosthetic biomaterials.
authors.affiliation: Nephrology Department, Hannover Medical School, Carl-Neuberg Str 1, 30625 Hannover, Germany. kiian.ioulia@mh-hannover.de
authors.forename: Yulia
authors.initials: Y
authors.lastname: Kiyan
authors.forename: Anne
authors.initials: A
authors.lastname: Limbourg
authors.forename: Roman
authors.initials: R
authors.lastname: Kiyan
authors.forename: Sergey
authors.initials: S
authors.lastname: Tkachuk
authors.forename: Florian P
authors.initials: FP
authors.lastname: Limbourg
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Ovsianikov
authors.forename: Boris N
authors.initials: BN
authors.lastname: Chichkov
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.forename: Inna
authors.initials: I
authors.lastname: Dumler
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004705:Endocytosis; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation; D015534:Trans-Activators / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014652:Vascular Diseases / Q000378:metabolism* / Q000473:pathology; D000099251:Myocardin
chemical_list: D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D015534:Trans-Activators; D014568:Urokinase-Type Plasminogen Activator; D000099251:Myocardin; C092317:RANGAP1 protein, human