Subendothelial cells from normal bovine arteries exhibit autonomous growth and constitutively activated intracellular signaling.
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, p21(ras), 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 A(2), 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.
Frid
M G
MG
Developmental Lung Biology Research Laboratory, Department of Pediatrics, University of Colorado Health Sciences Center, Denver 80262, USA. Maria.Frid@UCHSC.edu
Aldashev
A A
AA
Nemenoff
R A
RA
Higashito
R
R
Westcott
J Y
JY
Stenmark
K R
KR
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000166:cytology; D000077214:Becaplermin; D001798:Blood Proteins / Q000494:pharmacology; D002417:Cattle; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D048429:Cell Size / Q000502:physiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology*; D011464:Epoprostenol / Q000096:biosynthesis; D019204:GTP-Binding Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D007527:Isoenzymes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology; D010741:Phospholipases A / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D011651:Pulmonary Artery / Q000166:cytology; D017540:Tunica Media / Q000166:cytology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000925:Anticoagulants; D001798:Blood Proteins; D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D019332:Endothelin-1; D007527:Isoenzymes; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000077214:Becaplermin; D011464:Epoprostenol; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D019204:GTP-Binding Proteins; D015232:Dinoprostone