Role of cyclooxygenase‐1 and ‐2 in endothelium‐dependent contraction of atherosclerotic mouse abdominal aortas

Abstract

The objective of this study was to determine the role of cyclooxygenase (COX)-1 or -2 in endothelium-dependent contraction under atherosclerotic conditions. Atherosclerosis was induced in apoE knockout (apoE(-/-)) mice and those with COX-1(-/-) (apoE(-/-)-COX-1(-/-)) by feeding with high fat and cholesterol food. Aortas (abdominal or the whole section) were isolated for functional and/or biochemical analyses. As in non-atherosclerotic conditions, the muscarinic receptor agonist acetylcholine (ACh) evoked an endothelium-dependent, COX-mediated contraction following NO synthase (NOS) inhibition in abdominal aortic rings from atherosclerotic apoE(-/-) mice. Interestingly, COX-1 inhibition not only abolished such a contraction in rings showing normal appearance, but also diminished that in rings with plaques. Accordingly, only a minor contraction (<30% that of apoE(-/-) counterparts) was evoked by ACh (following NOS inhibition) in abdominal aortic rings of atherosclerotic apoE(-/-)-COX-1(-/-) mice with plaques, and none was evoked in those showing normal appearance. Also, the contraction evoked by ACh in apoE(-/-)-COX-1(-/-) abdominal aortic rings with plaques was abolished by non-selective COX inhibition, thromboxane-prostanoid (TP) receptor antagonism, or endothelial denudation. Moreover, it was noted that ACh evoked a predominant production of the prostacyclin (PGI2, which mediates abdominal aortic contraction via TP receptors in mice) metabolite 6-keto-PGF1α, which was again sensitive to COX-1 inhibition or COX-1(-/-). Therefore, in atherosclerotic mouse abdominal aortas, COX-1 can still be the major isoform mediating endothelium-dependent contraction, which probably results largely from PGI2 synthesis as in non-atherosclerotic conditions. In contrast, COX-2 may have only a minor role in such response limited to areas of plaques under the same pathological condition.

Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

“…3), we observed that Cox-1 prevails over Cox-2 in the mediation of the endothelium-dependent vasoconstrictor response to PE apoE -/- mice. This is in agreement with the finding that aortic endothelial cells preferentially express Cox-1 versus Cox-2 [31, 41], and that as Cox-1 expression is increased, the major source of vasoconstrictor prostanoids is converted into the endothelial cells, which diffuse to contract the underlying vascular smooth muscle in arteries of mouse models of cardiovascular diseases [31, 42]. Importantly, chronic treatment with sildenafil normalized the vascular hypercontractility (R max ) in this model of AT.…”

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

“…Prior studies showed that COX-derived products do not contribute to vasodilation in healthy resistance vessels in rodents 14 but are implicated in conduit vessel function in the setting of obesity and dyslipidemia. 30,37 We found that indomethacin does not affect acetylcholine-induced relaxation at baseline in small mesenteric resistance arteries or in mice exposed to risk factors regardless of their sex or the presence of EC-MR ( Figure 3). These data suggest that COX-derived products do not contribute to endothelium-dependent relaxation in mesenteric resistance microvessels in these obesity and hyperlipidemia models.…”

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

“…Thus, while its blood level could be lower than that of our in vivo studies, the amount of PGE 2 produced inside the vascular wall could easily reach a level (eg, the amount of PGE 2 produced in ACh-stimulated atherosclerotic mouse abdominal aorta is ~0.5 ng/mg or 1.35 μmol/kg tissue) required for activations of both EP3 (from ≤0.001 μM) and TP to regulate local vascular function or to buffer its general dilator effect systemically. 40 Furthermore, the unaltered maximal contraction in EP3 −/− arteries implies that the effect of PGE 2 via TP is more efficacious than that via EP3, explaining why PGE 2 evokes contraction at higher concentrations even in vessels where it initially elicits relaxation. 18,25 Meanwhile, the difference in effects between EP4 and EP2 antagonisms and that in mRNA expressions could be explained by EP4's mediating the vasodilator effect of PGE 2 on the renal vasculature 13,24,25 and the unintended effects that might be associated with prostanoid receptor antagonists.…”