© 1999 American Heart Association, Inc.
Vascular Biology |
Subendothelial Cells From Normal Bovine Arteries Exhibit Autonomous Growth and Constitutively Activated Intracellular Signaling
From the Developmental Lung Biology Research Laboratory, Department of Pediatrics (M.G.F., A.A.A., K.R.S.), and the Division of Renal Diseases and Hypertension, Department of Medicine (R.A.N., R.H.), University of Colorado Health Sciences Center, Denver; the Institute of Molecular Medicine (A.A.A.), National Center for Cardiology and Internal Medicine, Bishkek, Kyrgyzstan; and the Department of Medicine (J.Y.W.), National Jewish Medical and Research Center, Denver, Colo.
Correspondence to Maria G. Frid, PhD, Developmental Lung Biology Research Laboratory, University of Colorado Health Sciences Center, Box B131, 4200 E 9th Ave, Denver, CO 80262. E-mail Maria.Frid{at}UCHSC.edu
Abstract—The arterial media is comprised of heterogeneous smooth muscle cell (SMC) subpopulations with markedly different growth responses to pathophysiological stimuli. Little information exists regarding the intracellular signaling pathways that contribute to these differences. Therefore, we investigated the growth-related signaling pathways in a unique subset of subendothelial SMCs (L1 cells) from normal, mature, bovine arteries and compared them with those in "traditional" SMCs derived from the middle media (L2 SMCs). Subendothelial L1 cells exhibited serum-independent autonomous growth, not observed in L2 SMCs. Autonomous growth of L1 cells was driven largely by the constitutively activated extracellular signal–regulated kinase (ERK-1/2) cascade. Inhibition of upstream activators of ERKs (MAP kinase kinase-1, p21ras, receptor tyrosine kinases, and Gi protein–coupled receptors) led to suppression of autonomous growth in these cells. L1 cells also exhibited constitutive activation of important downstream targets of ERKs (cytosolic phospholipase A2, cyclooxygenase-2) and secreted large amounts of prostaglandins. Importantly, L1 cells secreted potent mitogenic factor(s), which could potentially contribute in an autocrine fashion to the constitutive activation of these cells. Our data suggest that unique arterial cells with autonomous growth potential and constitutively activated signaling pathways exist in normal arteries and may contribute selectively to the pathogenesis of vascular diseases.
Key Words: smooth muscle cell proliferation • heterogeneity • mitogen-activated protein kinase • G proteins • prostaglandins
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