title: PDGF-induced migration of vascular smooth muscle cells is inhibited by heme oxygenase-1 via VEGFR2 upregulation and subsequent assembly of inactive VEGFR2/PDGFRβ heterodimers.
abstract: OBJECTIVE
  In cardiovascular regulation, heme oxygenase-1 (HO-1) activity has been shown to inhibit vascular smooth muscle cell (VSMC) proliferation by promoting cell cycle arrest at the G1/S phase. However, the effect of HO-1 on VSMC migration remains unclear. We aim to elucidate the mechanism by which HO-1 regulates PDGFBB-induced VSMC migration.
  
  
  RESULTS
  Transduction of HO-1 cDNA adenoviral vector severely impeded human VSMC migration in a scratch, transmembrane, and directional migration assay in response to PDGFBB stimulation. Similarly, HO-1 overexpression in the remodeling process during murine retinal vasculature development attenuated VSMC coverage over the major arterial branches as compared with sham vector-transduced eyes. HO-1 expression in VSMCs significantly upregulated VEGFA and VEGFR2 expression, which subsequently promoted the formation of inactive PDGFRβ/VEGFR2 complexes. This compromised PDGFRβ phosphorylation and impeded the downstream cascade of FAK-p38 signaling. siRNA-mediated silencing of VEGFA or VEGFR2 could reverse the inhibitory effect of HO-1 on VSMC migration.
  
  
  CONCLUSIONS
  These findings identify a potent antimigratory function of HO-1 in VSMCs, a mechanism that involves VEGFA and VEGFR2 upregulation, followed by assembly of inactive VEGFR2/PDGFRβ complexes that attenuates effective PDGFRβ signaling.
authors.affiliation: Molecular Cardiology Laboratory, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Caroline
authors.initials: C
authors.lastname: Cheng
authors.forename: Remco A
authors.initials: RA
authors.lastname: Haasdijk
authors.forename: Dennie
authors.initials: D
authors.lastname: Tempel
authors.forename: Wijnand K
authors.initials: WK
authors.lastname: den Dekker
authors.forename: Ihsan
authors.initials: I
authors.lastname: Chrifi
authors.forename: Lau A J
authors.initials: LA
authors.lastname: Blonden
authors.forename: Esther H M
authors.initials: EH
authors.lastname: van de Kamp
authors.forename: M
authors.initials: M
authors.lastname: de Boer
authors.forename: Petra E
authors.initials: PE
authors.lastname: Bürgisser
authors.forename: Annemarie
authors.initials: A
authors.lastname: Noorderloos
authors.forename: Joost A P
authors.initials: JA
authors.lastname: Rens
authors.forename: Timo L M
authors.initials: TL
authors.lastname: ten Hagen
authors.forename: Henricus J
authors.initials: HJ
authors.lastname: Duckers
mesh_terms: D002465:Cell Movement; D049109:Cell Proliferation; D051547:Heme Oxygenase-1 / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D051547:Heme Oxygenase-1; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2