title: Protease-activated receptor-2 modulates protease-activated receptor-1-driven neointimal hyperplasia.
abstract: OBJECTIVE
  Emerging evidence suggests that protease-activated receptors-1 and -2 (PAR1 and PAR2) can signal together in response to proteases found in the rapidly changing microenvironment of damaged blood vessels. However, it is unknown whether PAR1 and PAR2 promote or mitigate the hyperplastic response to arterial injury. Using cell-penetrating PAR1 pepducins and mice deficient in PAR1 or PAR2, we set out to determine the respective contributions of the receptors to hyperplasia and phenotypic modulation of smooth muscle cells (SMCs) in response to arterial injury.
  
  
  RESULTS
  SMCs were strongly activated by PAR1 stimulation, as evidenced by increased mitogenesis, mitochondrial activity, and calcium mobilization. The effects of chronic PAR1 stimulation following vascular injury were studied by performing carotid artery ligations in mice treated with the PAR1 agonist pepducin, P1pal-13. Histological analysis revealed that PAR1 stimulation caused striking hyperplasia, which was ablated in PAR1(-/-) and, surprisingly, PAR2(-/-) mice. P1pal-13 treatment yielded an expression pattern consistent with a dedifferentiated phenotype in carotid artery SMCs. Detection of PAR1-PAR2 complexes provided an explanation for the hyperplastic effects of the PAR1 agonist requiring the presence of both receptors.
  
  
  CONCLUSIONS
  We conclude that PAR2 regulates the PAR1 hyperplastic response to arterial injury leading to stenosis.
authors.affiliation: Hemostasis and Thrombosis Laboratory, Molecular Oncology Research Institute, Tufts Medical Center, 75 Kneeland St, Boston, MA 02111, USA.
authors.forename: Leila M
authors.initials: LM
authors.lastname: Sevigny
authors.forename: Karyn M
authors.initials: KM
authors.lastname: Austin
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Shogo
authors.initials: S
authors.lastname: Kasuda
authors.forename: Georgios
authors.initials: G
authors.lastname: Koukos
authors.forename: Sheida
authors.initials: S
authors.lastname: Sharifi
authors.forename: Lidija
authors.initials: L
authors.lastname: Covic
authors.forename: Athan
authors.initials: A
authors.lastname: Kuliopulos
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation; D005260:Female; D006965:Hyperplasia / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000503:physiopathology; D058426:Neointima / Q000473:pathology* / Q000503:physiopathology*; D010641:Phenotype; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D044464:Receptor, PAR-2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D044463:Receptor, PAR-1; D044464:Receptor, PAR-2