Vascular bed heterogeneity in age‐related endothelial dysfunction with respect to NO and eicosanoids

Abstract

1 Endothelial dysfunction has been described with ageing but the mechanisms responsible have not been clearly elucidated and might be di erent from one vessel to the other. This study assesses the relative contribution of endothelial nitric oxide (NO) and cyclo-oxygenase (COX) metabolites in relaxation to acetylcholine with ageing in the aorta and the small mesenteric artery of the rat. 2 In the aorta and branch II or III of superior mesenteric artery (SMA), endothelium-dependent relaxation to acetylcholine was not di erent between 12 ± 14 (adult) and 32-week-old rats whereas it was reduced at 70 ± 100 (old) weeks of age. 3 Despite an increased endothelial NO-synthase protein expression, the NO-synthase inhibitor, N G -nitro-L-arginine-sensitive component of relaxation decreased with ageing. 4 In old rats, exposure to the COX inhibitor, indomethacin, but not the selective COX-2 inhibitor, NS-398, potentiated response to acetylcholine. The thromboxane A 2 /prostaglandin H 2 receptor antagonist, GR 32191B enhanced relaxation to acetylcholine in aorta but it had no e ect in SMA. Furthermore, acetylcholine increased thromboxane B 2 production (enzymeimmunoassay) in aorta but not in SMA. Finally, Western blot analysis showed enhanced expression of COX-1 and 2 in the two arteries with ageing. 5 These results suggest that the decrease in acetylcholine-induced relaxation with ageing involves reduced NO-mediated dilatation and increased generation of vasoconstrictor prostanoids most likely from COX-1. They also point out vascular bed heterogeneity related to the nature of prostanoids involved between the aorta (i.e., thromboxane A 2 ) and the SMA (unidenti®ed) arteries even though increased expression of COX occurs in both vessels.

Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis

“…Thus, in normotensive individuals, an earlier primary dysfunction of the NO pathway and a later production of oxidative stress cause age-related reduction in endothelium-dependent vasodilation; these alterations are similar but earlier in hypertensive patients compared with normotensive subjects (53). Furthermore, enhanced oxidative stress plays a critical role in the deleterious effect of aging on the endothelium through acceleration of NO breakdown by reactive oxygen species (8)(9)(10)(11)(12)(13)(14). Increased oxidative stress also occurs during vascular response to PTCA (54,55).…”

“…However, routine clinical management using pure NO donors could be difficult because of systemic effects on blood pressure. The mechanisms underlying restenosis are further complicated by vascular aging (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Decreased vasorelaxation caused by a decline in NO and endothelium-derived hyperpolarizing factor, as well as increased vasoconstriction mediated by cyclooxygenase products such as thromboxane A2, and concomitantly increased sensitivity of apoptosis, are likely to occur in aging (5-14, 52).…”

“…Decreased free NO levels in aged rat aortas are associated with increased formation of the toxic peroxynitrite (14). Transient increased endothelial NO-synthase activity could be a compensatory, but eventually futile, mechanism to counter-regulate the age-related loss of NO (9)(10)(11)(12)(13)(14). Therefore, arteries from aged living organs are predisposed to develop vascular lesions and have a reduced endogenous pathophysiological cascade of events leading to vascular protection.…”

“…This phenomenon could be related to a concurrent decrease in the bioavailability of the antiproliferative effect of nitric oxide (NO). Indeed, there is considerable growing experimental and clinical evidence that aging is also associated with a decline in the release of bioactive NO (9)(10)(11)(12)(13). Decreased free NO levels in aged rat aortas are associated with increased formation of the toxic peroxynitrite (14).…”

Participation of Prostacyclin in Endothelial Dysfunction Induced by Aldosterone in Normotensive and Hypertensive Rats

“…It has been reported that through the activation of TP receptors, vasoconstrictor prostanoids such as TXA 2 can participate in the endothelial dysfunction associated with different cardiovascular risk factors. 30,32,34 Incubation with SQ 29 548, a TP receptor antagonist, increased ACh relaxations in both strains of rats treated with aldosterone in a comparable manner, suggesting the participation of vasoconstrictor prostanoids through TP receptors. However, the present results showed that in aorta from WKY and SHR treated with aldosterone, TXA 2 is not an important candidate responsible for the reduction of endothelium-dependent relaxations.…”