EP3 Blockade Adds to the Effect of TP Deficiency in Alleviating Endothelial Dysfunction in Atherosclerotic Mouse Aortas

Abstract

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.

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

“…Mice were weighted before blood pressure measurements. Blood pressure was measured in mice of 8 weeks of age with a noninvasive, computerized tail‐cuff system (ALC‐NIBP, ALCBIO; Shanghai, China) as described previously . Briefly, mice were first accustomed to tail‐cuff blood pressure measurements for three consecutive days, and blood pressure was then measured on the 4th day in an examiner‐blinded manner.…”

“…Blood pressure was measured in mice of 8 weeks of age with a noninvasive, computerized tail-cuff system (ALC-NIBP, ALCBIO; Shanghai, China) as described previously. 36,37 Briefly, mice were first accustomed to tail-cuff blood pressure measurements for three consecutive days, and blood pressure was then measured on the 4th day in an examinerblinded manner. Systolic arterial and diastolic blood pressures (SBP and DBP, respectively) of each mouse were from the average of three measurements with similar values.…”

Differential properties of E prostanoid receptor‐3 and thromboxane prostanoid receptor in activation by prostacyclin to evoke vasoconstrictor response in the mouse renal vasculature

“…[8][9][10][11][12][13][14] It has now become clear that vasomotor reactions to PGI 2 can be collectively modulated by IP, the Tx prostanoid receptor (TP; the original receptor of TxA 2 that mediates vasoconstriction and platelet aggregation), and/or the E prostanoid receptor-3 (EP3; one of the original vasoconstrictor receptors of PGE 2 ); a contractile response to PGI 2 reflects vasoconstrictor activities of TP and/ or EP3 outweighing the dilator effect of IP. 11,[15][16][17][18][19] In many vascular beds including some critical vessels, for example, renal arteries, PGI 2 is recognized as an endothelium-derived contracting factor (EDCF) in health as well as in disease conditions. 9,17,[20][21][22][23][24][25][26][27] On the other hand, the concentration of PGI 2 to evoke vasoconstrictor activity has been noted to vary considerably among different vascular beds.…”

“…11,16,18,[20][21][22]26 However, in some vessels that show contraction to low concentration of PGI 2 , IP also has a significant functional presence. 15,19 Interestingly, the expression of EP3 has been found to vary considerably among vascular beds. 29,30 Moreover, vessels that contract to low concentrations of PGI 2 , such as renal arteries and abdominal aorta, show a common property in having a substantial expression or functional presence of EP3.…”

“…29,30 Moreover, vessels that contract to low concentrations of PGI 2 , such as renal arteries and abdominal aorta, show a common property in having a substantial expression or functional presence of EP3. 15,19,29,30 Thus, its higher potency on EP3 than on TP could be a reason for PGI 2 's evoking vasoconstrictor activity at low concentrations in these vessels. However, the initial concentration of PGI 2 to activate EP3 as compared to that of IP or TP has not been elucidated.…”