TP and/or EP3 receptors mediate the vasoconstrictor and pressor responses of prostaglandin F _2α in mice and/or humans

Abstract

The vasoconstrictor and/or pressor effects of prostaglandin (PG)F2α participate in the development of vascular pathologies and limit the clinical use of the agent. This study aimed to determine the receptor types responsible for the vasoconstrictor activity of PGF2α and whether they mediate the pressor response evoked by the prostanoid under in vivo conditions. Experiments were performed on genetically altered mice and/or on vessels from these mice or humans. Here we show that deletion of the thromboxane‐prostanoid receptor (TP−/−) abolished or drastically diminished the contraction to PGF2α in isolated mouse vessels (some of which were resistance arteries) and reduced the elevation in blood pressure evoked by the prostanoid under in vivo conditions. In accordance, TP antagonism abolished the contraction in small arteries of human omentum. Further deletion of E prostanoid receptor type 3 (EP3−/−) removed the PGF2α‐evoked contraction that remained in some TP−/− arteries and added to the effect of TP−/− on the elevation in blood pressure evoked by the prostanoid under in vivo conditions. In contrast, the uterine contraction to PGF2α mediated via the F prostanoid receptor (FP) was unaltered in TP−/−/EP3−/− mice. These results demonstrate that the non‐FP receptors TP and/or EP3 mediate the vasoconstrictor and pressor effects of PGF2α, which are still of concern under clinical conditions.—Liu, B., Li, J., Yan, H., Tian, D., Li, H., Zhang, Y., Guo, T., Wu, X., Luo, W., Zhou, Y. TP and/or EP3 receptors mediate the vasoconstrictor and pressor responses of prostaglandin F2α in mice and/or humans. FASEB J. 33, 2451–2459 (2019). http://www.fasebj.org

Prostaglandin E2sequentially activates E‐prostanoid receptor‐3 and thromboxane prostanoid receptor to evoke contraction and increase in resistance of the mouse renal vasculature

“…Indeed, compared to that of any other EP, EP1 −/− does not alter the effect of PGE 2 on systemic blood pressure . Meanwhile, the fact that EP3 is activated by PGE 2 from a very low concentration (≤0.001 μM) reflects a high affinity of the receptor for the prostanoid and is consistent with its being one of the prototype receptors of PGE 2 and its higher expression level in renal arteries compared to many other vessels revealed here or previously . Besides, the relaxation or increase of flow in TP −/− /EP3 −/− mice implies that the response to PGE 2 in mouse renal vasculature also contains a dilator effect masked.…”

“…This could be due to an influence of basal NO production as suggested elsewhere previously with other prostanoids or vasoconstrictor agonists. 17,20,31 More importantly, PGE 2 was found to cause a reduction of flow in NOS-uninhibited kidneys perfused under a constant pressure. It must be emphasized that this decrease of flow was not due to an increase in resistance of main renal arteries, which were cannulized under perfused conditions.…”

“…In addition, in NOS-inhibited WT vessels, PGE 2 (10 μM) evoked a contraction, which was reduced by the TP antagonist SQ29548 (10 μM; Figure 1C) that has an effect similar to that of TP −/− . 19 Notably, although both have a nonselective effect on TP, 18,20,35 the EP3 antagonist L798106 (1 μM) but not the EP1 antagonist SC19220 (10 μM) added to the effect of SQ29548, leading to an almost complete abolition of the contraction ( Figure 1C).…”

“…Vasomotor reaction was measured as described previously. 20 Briefly, the vascular ring was mounted between the two tungsten wires in an organ bath filled with PSS aerated with 95% O 2 -5% CO 2 and maintained at 37°C. One wire was stationary, whereas the other was connected to an AE801 force transducer (Kronex, Oakland, CA).…”

“…29,30 Moreover, we have recently shown that in mouse renal arteries where TP acts as a vasoconstrictor receptor of many different prostanoids, the expression level of EP3 is higher than that of many other vascular beds. 20,[31][32][33][34] Therefore, there is also a pressing need to determine the exact direct effect of PGE 2 on the overall renal vasculature and how each of these two prostanoid receptors (TP and EP3) is involved in the response.…”