Endothelial dysfunction, which leads to ischemic events under atherosclerotic conditions, can be attenuated by antagonizing the thromboxane-prostanoid receptor (TP) that mediates the vasoconstrictor effect of prostanoids including prostacyclin (PGI2). This study aimed to determine whether antagonizing the E prostanoid receptor-3 (EP3; which can also be activated by PGI2) adds to the above effect of TP deficiency (TP–/–) under atherosclerotic conditions and if so, the underlying mechanism(s). Atherosclerosis was induced in ApoE–/– mice and those with ApoE–/– and TP–/–. Here, we show that in phenylephrine pre-contracted abdominal aortic rings with atherosclerotic lesions of ApoE–/–/TP–/– mice, although an increase of force (which was larger than that of non-atherosclerotic controls) evoked by the endothelial muscarinic agonist acetylcholine to blunt the concurrently activated relaxation in ApoE–/– counterparts was largely removed, the relaxation evoked by the agonist was still smaller than that of non-atherosclerotic TP–/– mice. EP3 antagonism not only increased the above relaxation, but also reversed the contractile response evoked by acetylcholine in NO synthase-inhibited atherosclerotic ApoE–/–/TP–/– rings into a relaxation sensitive to I prostanoid receptor antagonism. In ApoE–/– atherosclerotic vessels the expression of endothelial NO synthase was decreased, yet the production of PGI2 (which evokes contraction via both TP and EP3) evoked by acetylcholine was unaltered compared to non-atherosclerotic conditions. These results demonstrate that EP3 blockade adds to the effect of TP–/– in uncovering the dilator action of natively produced PGI2 to alleviate endothelial dysfunction in atherosclerotic conditions.

Although recognized to have an in vivo vasodepressor effect blunted by the vasoconstrictor effect of E-prostanoid receptor-3 (EP3), prostaglandin E 2 (PGE 2 ) evokes contractions of many vascular beds that are sensitive to antagonizing the thromboxane prostanoid receptor (TP). This study aimed to determine the direct effect of PGE 2 on renal arteries and/or the whole renal vasculature and how each of these two receptors is involved in the responses. Experiments were performed on isolated vessels and perfused kidneys of wild-type mice and/or mice with deficiency in TP (TP −/− ), EP3 (EP3 −/− ), or both TP and EP3 (TP −/− /EP3 −/− ). Here we show that PGE 2 (0.001-30 μM) evoked not only contraction of main renal arteries, but also a decrease of flow in perfused kidneys. EP3 -/diminished the response to 0.001-0.3 μM PGE 2 , while TP −/− reduced that to the prostanoid of higher concentrations. In TP −/− /EP3 −/− vessels and perfused kidneys, PGE 2 did not evoke contraction but instead resulted in vasodilator responses. These results demonstrate that PGE 2 functions as an overall direct vasoconstrictor of the mouse renal vasculature with an effect reflecting the vasoconstrictor activities outweighing that of dilation. Also, our results suggest that EP3 dominates the vasoconstrictor effect of PGE 2 of low concentrations (≤0.001-0.3 μM), but its effect is further added by that of TP, which has a higher efficacy, although activated by higher concentrations (from 0.01 μM) of the same prostanoid PGE 2 . K E Y W O R D S EP3, gene deficiency, PGE 2 , renal vasoconstriction, TP | 2569 LIU et aL. How to cite this article: Liu B, Wu X, Zeng R, et al. Prostaglandin E 2 sequentially activates E-prostanoid receptor-3 and thromboxane prostanoid receptor to evoke contraction and increase in resistance of the mouse renal vasculature.

Vasomotor reactions of prostacyclin (prostaglandin I 2 ; PGI 2) can be collectively modulated by thromboxane prostanoid receptor (TP), E-prostanoid receptor-3 (EP3), and the vasodilator I prostanoid receptor (IP). This study aimed to determine the direct effect of PGI 2 on renal arteries and/or the whole renal vasculature and how each of these receptors is involved. Experiments were performed on vessels or perfused kidneys of wild-type mice and/or mice with deficiency in TP (TP −/−) and/ or EP3. Here we show that PGI 2 did not evoke relaxation, but instead resulted in contraction of main renal arteries (from ~0.001-0.01 µM) or reduction of flow in perfused kidneys (from ~1 µM); either of them was reversed into a dilator response in TP −/− /EP3 −/− counterparts. Also, we found that in renal arteries although it has a lesser effect than TP −/− on the maximal contraction to PGI 2 (10 µM), EP3 −/− but not TP −/− resulted in relaxation to the prostanoid at 0.01-1 µM. Meanwhile, TP −/− only significantly reduced the contractile activity evoked by PGI 2 at ≥0.1 µM. These results demonstrate that PGI 2 may evoke an overall vasoconstrictor response in the mouse renal vasculature, reflecting activities of TP and EP3 outweighing that of the vasodilator IP. Also, our results suggest that EP3, on which PGI 2 can have a potency similar to that on IP, plays a major role in the vasoconstrictor effect of the prostanoid of low concentrations (≤1 µM), while TP, on which PGI 2 has a lower potency but higher efficacy, accounts for a larger part of its maximal contractile activity.

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The F prostanoid receptor (FP), which accounts for the therapeutic effect of PGF2α in uterine atony that leads to postpartum hemorrhage and maternal morbidity, could possibly mediate vasoconstrictor effect in small or resistance arteries to elevate blood pressure that limits the clinical use of the agent in patients with cardiovascular disorders. This study aimed to test the above hypothesis with genetically altered mice. Ex vivo and in vivo experiments were performed on control wild‐type (WT) mice and mice with deficiencies in FP (FP−/−) or thromboxane (Tx)‐prostanoid receptor (the original receptor of TxA2; TP−/−), and/or those with an additional deficiency in E prostanoid receptor‐3 (one of the vasoconstrictor receptors of PGE2; EP3−/−). Here, we show that PGF2α indeed evoked vasoconstrictor responses in the above‐mentioned tissues of WT mice, which were however unaltered by FP−/−. Interestingly, such contractile responses were reversed into dilations by TP−/−/EP3−/−. A similar pattern of results was observed with the pressor effect of PGF2α under in vivo conditions. However, TP−/− alone (which could largely remove the contractile responses) did not result in relaxation to PGF2α. Also, either the ex vivo vasodilator effect or the in vivo depressor response of PGF2α obtained after the removal of TP and EP3‐mediated actions was unaltered by FP−/−. Therefore, both the ex vivo vasoconstrictor action in small or resistance arteries and the systemic pressor effect of PGF2α can reflect vasoconstrictor activities derived from the non‐FP receptors TP and EP3 outweighing a concurrently activated dilator effect, which is again independent of FP.