Dissociation of the contractile and hypertrophic effects of vasoconstrictor prostanoids in vascular smooth muscle

To more clearly define the physiologic roles of thromboxane (TX)A2 and primary prostaglandins (PG) in vascular tissue we examined vascular contractility, cell signaling, and growth responses. The growth-promoting effects of (15S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid (U46...

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Bibliographic Details
Published in:The Journal of biological chemistry 1992-12, Vol.267 (34), p.24897-24905
Main Authors: G W Dorn, 2nd, M W Becker, M G Davis
Format: Article
Language:English
Subjects:
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Animals
Aorta - cytology
Aorta - drug effects
Aorta - physiology
Binding, Competitive
Biochemistry & Molecular Biology
Biological and medical sciences
Calcium - metabolism
Cell physiology
Cells, Cultured
Cytosol - metabolism
Dinoprost - pharmacology
Dinoprostone - pharmacology
DNA - biosynthesis
Fundamental and applied biological sciences. Psychology
Hypertrophy
Inositol Phosphates - metabolism
Isometric Contraction - drug effects
Kinetics
Leucine - metabolism
Life Sciences & Biomedicine
Male
Molecular and cellular biology
Muscle, Smooth, Vascular - cytology
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - physiology
Prostaglandin Endoperoxides, Synthetic - pharmacology
Prostaglandins - pharmacology
Protein Biosynthesis
Rats
Rats, Sprague-Dawley
Receptors, Prostaglandin - metabolism
Receptors, Thromboxane - metabolism
Responses to growth factors, tumor promotors, other factors
Science & Technology
Thymidine - metabolism
Vasoconstrictor Agents - pharmacology
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Summary:To more clearly define the physiologic roles of thromboxane (TX)A2 and primary prostaglandins (PG) in vascular tissue we examined vascular contractility, cell signaling, and growth responses. The growth-promoting effects of (15S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619; TXA2 agonist), PGF2 alpha, and PGE2 consisted of protein synthesis and proto-oncogene expression, but not DNA synthesis or cell proliferation. U46619 contracted rat aortas and increased cultured rat aortic vascular smooth muscle cell intracellular free calcium concentration [Ca2+]i, [3H]inositol monophosphate (IP) accumulation, myosin light chain phosphorylation, and protein synthesis ([3H]leucine incorporation) with EC50 values ranging from 10 to 50 nM. Each of these responses was inhibitable with the TXA2 receptor antagonist [1S]1 alpha,2 beta(5Z),3 beta,4 alpha-7-(3-[2- [(phenylamino)carbonyl]hydrazino]methyl)-7-oxabicyclo[2.2.1]hept-2- yl-5-heptenoic acid (SQ29548). In contrast, PGF2 alpha increased [Ca2+]i, [3H]IP, and protein synthesis with EC50 values of 30-230 nM but contracted rat aortas with an EC50 of 4800 nM. PGE2 increased [Ca2+]i, [3H]IP accumulation, protein synthesis, and contracted rat aortas with EC50 values of 2.5-3.5 microM. TXA2 receptor blockade prevented PGF2 alpha- and PGE2-induced aortic contraction and cell myosin light chain phosphorylation, but not cell signaling or protein synthesis. Binding studies to vascular smooth muscle TXA2 receptors using 1S-[1 alpha,2 beta(5Z),3 alpha(1E,3S),4 alpha]-7-(3-[3-hydroxy-4-(p- [125I]iodophenoxy)-1-butenyl]7-oxabicyclo[2.2.1]hept-2-yl)-5-hepte noic acid ([125I]BOP) showed U46619, SQ29548, PGF2 alpha, and PGE2 competition for TXA2 receptor binding at concentrations similar to their EC50 values for aortic contraction, while binding competition with [3H]PGF2 alpha and [3H]PGE2 demonstrated the specificity of [125I]BOP and SQ29548 for TXA2 receptors. The results suggest that 1) PGF2 alpha- and E2-stimulated vessel contraction is due to cross-agonism at vascular TXA2 receptors; 2) PGF2 alpha stimulates TXA2 receptor-independent vascular smooth muscle protein synthesis at nanomolar concentrations, consistent with an interaction at its primary receptor; and 3) TXA2 is a potent stimulus for vascular smooth muscle contraction and protein synthesis. We suggest that the main physiologic effect of PGF2 alpha may be as a stimulus for vascular smooth muscle cell hypertrophy, not as a contractile agonist.
ISSN:0021-9258
1083-351X
DOI:10.1016/s0021-9258(18)35848-4