Role of formic receptors in soluble urokinase receptor-induced human vascular smooth muscle migration

Enrico A. Duru, Yuyang Fu, Mark G. Davies

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background Vascular smooth muscle cell (VSMC) migration in response to urokinase is dependent on binding of the urokinase molecule to the urokinase plasminogen receptor (uPAR) and cleavage of the receptor. The aim of this study was to examine the role of the soluble uPAR (suPAR) in VSMC migration. Methods Human VSMCs were cultured in vitro. Linear wound and Boyden microchemotaxis assays of migration were performed in the presence of suPAR. Inhibitors to G-protein signaling and kinase activation were used to study these pathways. Assays were performed for mitogen-activated protein kinase and epidermal growth factor receptor activation. Results suPAR induced concentration-dependent migration of VSMC, which was G protein-dependent and was blocked by Gαi and Gβγ inhibitors. Removal of the full uPAR molecule by incubation of the cells with a phospholipase did not interfere with this response. suPAR induced ERK1/2, p38MAPK, and c-Jun N-terminal kinase [JNK] activation in a Gαi/Gβγ-dependent manner, and interruption of these signaling pathways prevented suPAR-mediated migration. suPAR activity was independent of plasmin activity. suPAR did not activate epidermal growth factor receptor. Interruption of the low affinity N-formyl-Met-Leu-Phe receptor (FPRL1) but not high affinity N-formyl-Met-Leu-Phe receptor (FPR) prevented cell migration and activation in response to suPAR. suPAR increased matrix metalloproteinase-2 expression and activity, and this was dependent on the low affinity N-formyl-Met-Leu-Phe receptor (FPRL1) and ERK1/2. Conclusions suPAR induces human smooth muscle cell activation and migration independent of the full uPAR through activation of the G protein-coupled receptor FPRL1, which is not linked to the plasminogen activation cascade.

Original languageEnglish (US)
Pages (from-to)396-405
Number of pages10
JournalJournal of Surgical Research
Volume195
Issue number2
DOIs
StatePublished - May 15 2015
Externally publishedYes

Keywords

  • Cell signaling
  • Human coronary smooth muscle cell
  • Migration
  • Soluble uPAR
  • uPA

ASJC Scopus subject areas

  • Surgery

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