Evidence for prostacyclin and cAMP upregulation by bradykinin and insulin-like growth factor 1 in vascular smooth muscle cells.

Although bradykinin (BK) and insulin like growth factor-1 (IGF-1) have been shown to modulate the functional and structural integrity of the arterial wall, the cellular mechanisms through which this regulation occurs is still undefined. The present study examined the role of second messenger molecules generated by BK and IGF-1 that could ultimately result in proliferative or antiproliferative signals in vascular smooth muscle cells (VSMC). Activation of BK or IGF-1 receptors stimulated the synthesis and release of prostacyclin (PGI(2)) leading to increased production of cAMP in VSMC. Inhibition of p42/p44(mapk) or src kinases prevented the increase in PGI(2) and cAMP observed in response to BK or IGF-1, indicating a role for these kinases in the regulation of cPLA(2) activity in the VSMC. Inhibition of PKC failed to alter production of PGI(2) in response to BK, but further increased both p42/p44(mapk) activation and the synthesis of PGI(2) produced in response to IGF-1. In addition, both BK and IGF-1 significantly induced the expression of c-fos mRNA levels in VSMC, and this effect of BK was accentuated in the presence a cPLA(2) inhibitor. Finally, inhibition of cPLA(2) activity and/or cyclooxygenase activity enhanced the expression of collagen I mRNA levels in response to BK and IGF-1 stimulation. These findings indicate that the effect of BK or IGF-1 to stimulate VSMC growth is an integrated response to the activation of multiple signaling pathways. Thus, the excessive cell growth that occurs in certain forms of vascular disease could reflect dysfunction in one or more of these pathways.