Abstract
Prostacyclin, also termed as prostaglandin I2 (PGI2), evokes contraction in vessels with limited expression of the prostacyclin receptor. Although the thromboxane-prostanoid receptor (TP) is proposed to mediate such a response of PGI2, other unknown receptor(s) might also be involved. TP knockout (TP−/−) mice were thus designed and used to test the hypothesis. Vessels, which normally show contraction to PGI2, were isolated for functional and biochemical analyses. Here, we showed that the contractile response evoked by PGI2 was indeed only partially abolished in the abdominal aorta of TP−/− mice. Interestingly, further antagonizing the E-type prostaglandin receptor EP3 removed the remaining contractile activity, resulting in relaxation evoked by PGI2 in such vessels of TP−/− mice. These results suggest that EP3 along with TP contributes to vasoconstrictor responses evoked by PGI2, and hence imply a novel mechanism for endothelial cyclooxygenase metabolites (which consist mainly of PGI2) in regulating vascular functions.
Highlights
On the other hand, in some vascular beds, PGI2 or endothelial COX metabolites evoke contraction via the activation of TP7–24
Sequencing of thromboxane-prostanoid receptor (TP) DNA PCR products revealed that as compared with that of wild-type (WT) mice, exon 3 of the TP locus in TP−/− mice has a 22 bp fragment deletion (CTG GGG GCC TGC TTT CGC CCG G) in the coding area, which was 18 bp after the start codon (NCBI Reference Sequence: NM_009325.3). This resulted in a frame-shift in TP mRNA transcript and a premature termination of protein translation (only 7 amino acids were coded before the appearance of a stop codon (TGA) in TP−/− mice; Fig. 1a, bottom right)
In this study we show that in NO synthase (NOS)-inhibited WT mouse abdominal aortas PGI2- or ACh evokes contraction that is diminished in TP−/− counterparts
Summary
In some vascular beds (including certain human vessels), PGI2 or endothelial COX metabolites (which consist mainly of PGI2) evoke contraction via the activation of TP7–24. Studies have further revealed that vasomotor reactions to PGI2 are modulated by both IP and TP; a vasoconstrictor response evoked by PGI2 or endothelial COX metabolites reflects limited expression or function of IP, which leads to the uncovering of vasoconstrictor activity derived from concurrently activated TP8,20–22,25–32. In some vascular beds, the contraction evoked by PGI2 or endothelial COX metabolites is less sensitive to TP blockade[11,22]. We propose that in addition to TP, other receptor(s) can be involved in PGI2-evoked vasoconstrictor activity. The involvement of TP in the vasoconstrictor activity of PGI2 has been primarily based on results with pharmacological blockade, which inhibits contractions evoked by other PGs or AA-related metabolites[8,33,34]. Carotid and/or renal arteries, where PGI2 evokes vasoconstrictor response under normal conditions[26,28,30,35], were isolated for biochemical and/or functional analyses
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