Induction of vascular smooth muscle cell growth by selective activation of the proteinase activated receptor-2 (PAR-2).
The proteinase-activated receptor (PAR-2) which belongs to the family of proteolytically cleaved receptors is activated by trypsin and by a synthetic peptide (SLIGKV) derived from the new amino terminus. Here, we have studied the mitogenic effect of trypsin and of SLIGKV on human aortic smooth muscle cells (SMC). Like trypsin, SLIGKV was a potent mitogen for SMC and exhibited the same activity as that of SFLLRN, a peptide mimicking the new amino terminus created by cleavage of the thrombin receptor. SLIGKV stimulated the proliferation of growth-arrested SMCs with a half-maximum mitogenic response at 80 nM. Under the same experimental conditions, the retro analogue or SLIGKV (VKGILS) did not show any mitogenic activity. Two specific inhibitors of the enzymatic activity of trypsin, alpha 1-antitrypsin and aprotinin, specifically inhibited trypsin-induced SMC growth (IC50 = 0.87 +/- 0.09 and 0.74 +/- 0.11 microM, respectively) but remain without effect on the mitogenic effect of the agonist peptide. The mitogenic effect of trypsin and SLIGKV was due to the release of platelet derived growth factor as demonstrated by the inhibitory activity of a neutralizing monoclonal anti-PGDF-BB antibody. These results demonstrate that the mitogenic effect of trypsin for SMCs is intimately linked to its esterolytic activity and mediated by the activation of PAR-2.
Bono
F
F
Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
Lamarche
I
I
Herbert
J M
JM
D001011:Aorta; D002455:Cell Division / Q000187:drug effects; D006133:Growth Substances / Q000378:metabolism*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D044464:Receptor, PAR-2; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology; D014357:Trypsin / Q000494:pharmacology
D006133:Growth Substances; D009842:Oligopeptides; D010446:Peptide Fragments; D044464:Receptor, PAR-2; D011956:Receptors, Cell Surface; D018179:Receptors, Thrombin; C109968:seryl-leucyl-isoleucyl--glycyl-lysyl-valine; D014357:Trypsin; D013917:Thrombin