INHIBITION OF VASCULAR SMOOTH-MUSCLE CELL-MIGRATION BY PEPTIDE AND ANTIBODY ANTAGONISTS OF THE ALPHA(V)BETA(3) INTEGRIN COMPLEX IS REVERSEDBY ACTIVATED CALCIUM CALMODULIN-DEPENDENT PROTEIN-KINASE-II/

The migration of vascular smooth muscle cells (VSMCs) is thought to pl ay a key role In the pathogenesis of many vascular diseases and is reg ulated by soluble growth factors/ chemoattractants as well as interact ions with the extracellular matrix. We have studied the effects of ant ibodies to rat beta 3 and human alpha(v) beta(3) integrins on the migr ation of VSMCs. Both integrin antibodies as well as cyclic RGD peptide s that bind to the vitronectin receptors alpha(v) beta(3) and alpha(v) beta(5) significantly inhibited PDGF-directed migration. This resulte d in a reduction in the accumulation of inositol (1,4,5) trisphosphate and the activation of calcium/calmodulin-dependent protein kinase II (CamKII), an important regulatory event in VSMC migration identified p reviously. PDGF-directed VSMC migration in the presence of the anti-in tegrin antibodies and cyclic RGD peptides was restored when intracellu lar CamKII activity was elevated by either raising intracellular calci um levels with the ionophore, ionomycin, or infecting with a replicati on-defective recombinant adenovirus expressing a constitutively activa ted CamKII cDNA (AdCMV.CKIID3). Rescue of rat VSMCs was also observed in stably transfected cell lines expressing constitutively activated b ut not wild-type CamKII, These observations identify a key intermediat e in the regulation of VSMC migration by outside-in signaling from the integrin alpha(v) beta(3).