Subendothelial cells from normal bovine arteries exhibit autonomous growthand constitutively activated intracellular signaling

The arterial media is comprised of heterogeneous smooth muscle cell (SMC) s ubpopulations with markedly different growth responses to pathophysiologica l stimuli. Little information exists regarding the intracellular signaling pathways that contribute to these differences. Therefore, we investigated t he growth-related signaling pathways in a unique subset of subendothelial S MCs (L1 cells) from normal, mature, bovine arteries and compared them with those in "traditional" SMCs derived from the middle media (L2 SMCs). Subend othelial LI cells exhibited serum-independent autonomous growth, not observ ed in L2 SMCs. Autonomous growth of L1 cells was driven largely by the cons titutively activated extracellular signal-regulated kinase (ERK-1/2) cascad e. Inhibition of upstream activators of ERKs (MAP kinase kinase-l, p21(ras) , receptor tyrosine kinases, and Gi protein-coupled receptors) led to suppr ession of autonomous growth in these cells, L1 cells also exhibited constit utive activation of important downstream targets of ERKs (cytosolic phospho lipase A(2), cyclooxygenase-2) and secreted large amounts of prostaglandins , Importantly, L1 cells secreted potent mitogenic factor(s), which could po tentially contribute in an autocrine fashion to the constitutive activation of these cells. Our data suggest that unique arterial cells with autonomou s growth potential and constitutively activated signaling pathways exist in normal arteries and may contribute selectively to the pathogenesis of vasc ular diseases.