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

G. W. Dorn, M. W. Becker, M. G. Davis

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

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-11α,9α-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619; TXA2 agonist), PGF(2α), 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] 1α,2β(5Z),3β,4α-7- (3-{2-[(phenylamino)carbonyl]hydrazino}methyl)-7-oxabicyclo[2.2.1]hept-2- yl-5-heptenoic acid (SQ29548). In contrast, PGF(2α) 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 μM. TXA2 receptor blockade prevented PGF(2α)- 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- [1α,2β(5Z),3α(1E,3S),4α]-7-{3-[3-hydroxy-4-(p-[125I]iodophenoxy)-1- butenyl]7-oxabicyclo[2.2.1]hept-2-yl}-5-heptenoic acid ([125I]BOP) showed U46619, SQ29548, PGF(2α), and PGE2 competition for TXA2 receptor binding at concentrations similar to their EC50 values for aortic contraction, while binding competition with [3H]PGF(2α) and [3H]PGE2 demonstrated the specificity of [125I]BOP and SQ29548 for TXA2 receptors. The results suggest that 1) PGF(2α)- and E2-stimulated vessel contraction is due to cross-agonism at vascular TXA2 receptors; 2) PGF(2α) 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 PGF(2α) may be a stimulus for vascular smooth muscle cell hypertrophy, not as a contractile agonist.

Original languageEnglish
Pages (from-to)24897-24905
Number of pages9
JournalJournal of Biological Chemistry
Volume267
Issue number34
StatePublished - 1992

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