Abstract
Estrogen (E) has been identified in epidemiologic and prospective studies to protect against the development of cardiovascular disease in women. It is unclear whether progesterone (P) is similarly beneficial. The mechanisms by which E or P might act are incompletely defined. One possibility is that sex steroids inhibit the proliferation of vascular smooth muscle, an early/important event in vascular pathology. We examined the ability of E and P to inhibit the growth of human umbilical vein smooth muscle cells (hUVSMC) in culture, when stimulated by serum or the mitogen, endothelin-1 (ET-1). Serum and ET-1 stimulated hVSMC cell numbers by approximately 110% and 43% respectively, compared with control, after 3 days in culture. This stimulation was maximally reversed 75% by E and 64% by P. No synergistic or additive effects of the two steroids were found. ET-1 and serum stimulated mitogen-activated protein kinase (MAP-K) and MAP-kinase kinase activities, and these were critical for mitogenesis. Mitogen-stimulated MAP-kinase kinase and MAP-K activities were significantly inhibited by either E or P. The steroids also inhibited mitogen-stimulated c-fos and c-myc, downstream targets for MAP-K action. Critical signaling and molecular events through which mitogens stimulate VSMC proliferation can be significantly inhibited by E or P, providing a potential cellular mechanism for their vascular protective actions.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Blotting, Northern
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Calcium-Calmodulin-Dependent Protein Kinases / physiology
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Cell Division / drug effects
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Cell Division / physiology
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Cells, Cultured
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DNA / metabolism
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Endothelin-1 / pharmacology
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Enzyme Activation
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Estrogens / pharmacology*
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Female
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Gene Expression Regulation / drug effects
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Genes, fos / genetics
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Genes, myc / genetics
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Humans
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Mitogen-Activated Protein Kinase Kinases
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Mitogens / pharmacology
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Muscle, Smooth, Vascular / chemistry
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Muscle, Smooth, Vascular / cytology*
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Muscle, Smooth, Vascular / drug effects*
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Pregnancy
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Progesterone / pharmacology*
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Protein Kinases / metabolism
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Protein Kinases / physiology
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Proto-Oncogene Proteins c-fos / analysis
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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Proto-Oncogene Proteins c-myc / analysis
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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Serum Albumin, Bovine / pharmacology
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Thymidine / metabolism
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Tritium
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Umbilical Veins / chemistry
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Umbilical Veins / cytology
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Umbilical Veins / drug effects
Substances
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Endothelin-1
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Estrogens
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Mitogens
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Proto-Oncogene Proteins c-fos
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Proto-Oncogene Proteins c-myc
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Tritium
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Serum Albumin, Bovine
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Progesterone
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DNA
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Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase Kinases
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Thymidine