Inhibition of human and rabbit arterial smooth muscle cell migration mediated by the kinin B1 receptor: role of receptor density and released mediators.

Bradykinin (BK)-related peptides are suspected to negatively influence diverse functions in vascular smooth muscle cells (SMCs), notably via stimulation of the inducible B1 receptor (B1R), and have been shown to inhibit the migration of rat SMCs. The present study had several objectives: (i) to test whether B1R mediates the inhibition of migration of arterial SMCs from additional species (the human and the rabbit); (ii) whether B1R density influences this action and whether autocrine NO or prostanoid release modulate it; and (iii) the possible signaling interaction between the B1R and phosphatidylinositol-3 kinase (PI-3K) has been addressed. The peptidase resistant B1R agonist Sar-[D-Phe8]des-Arg9-BK (10 nmol/L - 1 micromol/L) was an inhibitor of migration in human or rabbit arterial SMCs in a wound closure assay, more effectively if the medium composition allowed a high B1R expression (20% fetal bovine serum (FBS) + interleukin-1beta (IL-1beta) in human SMCs, 10% FBS in rabbit cells). The effect of the B1R agonist on motility was abrogated by a B1R antagonist, B-9858, but not by the B2R antagonist Hoe 140; a peptidase-resistant B2R agonist, [Phe8Psi(CH2-NH)-Arg9]BK, had a marginal or no effect on migration. Sar-[D-Phe8]des-Arg9-BK (1 micromol/L) did not significantly influence SMC proliferation. The B1R-mediated inhibition of SMC migration was not affected by pharmacological inhibition of the nitric oxide synthases or cyclooxygenases-1 or -2, but was correlated to an inhibition of PI-3K in both types of SMCs. The inhibition of SMC migration mediated by the kinin B1R is likely independent from NO or prostanoid release, applicable to several species, and correlated to receptor density and the inhibition of PI-3K.