The n-3 PUFAs, EPA and DHA, found in fish and supplements are reported to improve vasodilation through different mechanisms that promote endothelial function and vascular reactivity [ 27 ]. We did this in both resistance and conduit arteries of rats since studies suggest that the vasodilation mechanisms can differ depending upon the type of artery [ 31 ].
Therefore, we investigated both types of blood vessel to fully understand the mechanisms involved with n-3 PUFA mediated relaxation. Endothelium has an important role in the regulation of vascular tone since it is involved in the production of various vasodilators including NO, PGI 2 and EETs, along with the transmission of endothelial hyperpolarization to VSMCs via myoendothelial gap junctions [ 2 — 5 ].
We investigated the effect of endothelial removal in n-3 PUFA mediated relaxation of rat aorta and mesenteric arteries. This is consistent with numerous reports suggesting that n-3 PUFAs can improve endothelial function and augment endothelium dependent relaxation [ 15 , 27 — 29 , 42 ]. However, relaxation was only partially inhibited following removal of endothelium and a large residual relaxation remained indicating that the vasodilator effect of n-3 PUFAs is primarily endothelium-independent.
Furthermore, as DHA-induced relaxation remained unaltered following endothelium removal in the aorta Fig 1C , there is heterogeneity in the vasodilator mechanisms of DHA between conduit and resistance arteries. For example, EPA was reported to induce calcium-independent increases in NO resulting in relaxation of bovine coronary arteries [ 43 ].
Clinical studies have validated these findings, indicating that long-term EPA treatment in patients with coronary artery disease improved both NO-dependent and -independent vasodilation [ 29 ]. For example a study investigating the effect of DHA supplementation in orchidectomized animals [ 46 ] found that vasodilator responses and NO levels were significantly lower in orchidectomized rats compared to the control rats and that DHA normalized these levels [ 46 ]. Additionally, in placental tissue derived from pregnancy-induced hypertensive rats with impaired vasodilator responses, n-3 PUFA supplementation led to an increase in eNOS levels [ 47 ].
Therefore, it is possible that the beneficial effects of n-3 PUFAs on NO production can only be observed in conditions where NO bioavailability is compromised. We believe our study indicates that n-3 PUFAs do not affect eNOS-mediated relaxations when acutely applied to arterial tissue from healthy animals and highlights that care must be taken when comparing n-3 PUFA effects between species and disease models. Both DHA and EPA compete with AA as substrates for COX enzymes resulting in the production of vasoactive metabolites and clinical evidence demonstrates there is altered prostanoid production as a result of fish oil supplementation in humans [ 49 ].
Furthermore, n-3 PUFAs inhibit noradrenaline- and angiotensin II-induced vasoconstriction of human forearm resistance vessels, an effect that is sensitive to COX blockade [ 49 ]. There is evidence indicating that ageing is associated with endothelial dysfunction and therefore is a risk factor for CVDs [ 52 ].
Various studies have indicated that ageing can evoke biochemical changes in the blood vessels resulting in impairment of NO production and PGI 2 -induced relaxation [ 53 — 57 ]. Therefore, it is possible that ageing could also affect the mechanisms involved with n-3 PUFA-induced vasodilation [ 58 ]; for example, the COX metabolites of n-3 PUFAs may have a more profound effect in improving the impaired endothelial function in older rats and this may partly explain the discrepancy. This study was conducted with rats of the same age and weight as used in our study. Further investigation is required to examine if different vasoconstrictor agonists and age groups of WKY rats alter the mechanisms underlying n-3 PUFA mediated vasodilation.
These findings again indicate heterogeneity in the vasodilation mechanisms of n-3 PUFAs.
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The lack of effect on DHA mediated relaxation and the large proportion of relaxation remaining following the blockade of CYP in EPA mediated relaxation, suggests other mechanisms are also involved. However, we cannot eliminate the possibility that metabolism by other enzymes, such as lipoxygenase, could contribute to these relaxation responses [ 61 ]. In this study, we also investigated if mechanisms of EDH-mediated relaxation could be involved with the vasodilation effect of n-3 PUFAs.
Consistent with these studies, our results demonstrate that DHA-mediated relaxations in both mesenteric artery and aorta have a component sensitive to the blockade of BK Ca Figs 4A and 5A. The lack of any effect on EPA-induced relaxation following BK Ca inhibition in the aorta indicates that direct or indirect modulation of this channel by EpETEs does not occur in this artery; again demonstrating the heterogeneity in the vasodilator mechanisms of n-3 PUFA mediated responses, depending upon both the type of artery and the n-3 PUFAs used to evoke relaxation. It is worth noting that we preconstricted arteries with U and that activation of TP receptors inhibits SK Ca channel activity in rat cerebral [ 64 ] and mesenteric arteries [ 65 ].
We cannot fully explain this discrepancy, but arterial IK Ca channels are restricted to signalling microdomains in the endothelium where activation of associated proteins regulates IK Ca -mediated hyperpolarization [ 67 , 68 ]. The endothelium-independent vasodilation mechanisms of n-3 PUFAs in arteries have not been extensively studied and remain unclear.
However, other endothelium-independent mechanisms for n-3 PUFA induced relaxation have been reported, for example, via inhibition of calcium influx in sheep pulmonary artery [ 69 ]. Furthermore, n-3 PUFAs are known to activate protein kinases such as protein kinase G, as demonstrated in cardiac fibroblasts [ 70 ].
If n-3 PUFAs are involved in activation of protein kinase G in arteries, they would also indirectly activate BK Ca [ 71 — 74 ] which would be consistent with our findings. Protein kinase A can also evoke vasodilation, through direct activation of vascular K ATP [ 77 ], therefore it can be speculated that n-3 PUFAs could also have an indirect interaction with potassium channels through the modulation of protein kinases, presenting an avenue for future investigation.
The aim of this study was to characterise the mechanisms of DHA- and EPA-dependent vasodilation in rat conduit and resistance arteries.
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These findings are summarised in Fig 6 and they clearly demonstrate heterogeneity in the vasodilation mechanisms of n-3 PUFAs depending upon both the type of n-3 PUFA and the vascular bed. In conclusion, our study provides evidence of significant heterogeneity in the mechanisms of n-3 PUFA mediated relaxation in rat aorta and mesenteric artery along with a novel role for IK Ca. We believe these findings will be invaluable for the design of future vascular studies that involve the use of n-3 PUFAs.
Solid arrows represent pathways that have been previously investigated whereas dotted arrows represent hypothetical pathways based on our findings. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Background and purpose Increasing evidence suggests that the omega-3 polyunsaturated acids n-3 PUFA , docosahexaenoic acid DHA and eicosapentaenoic acid EPA , are beneficial to cardiovascular health, promoting relaxation of vascular smooth muscle cells and vasodilation.
Methods Wire myography was used to measure the vasomotor responses of freshly dissected rat mesenteric artery and aorta. Role of endothelium in n-3 PUFA-dependent relaxation of rat mesenteric artery and aorta Endothelium has a critical role in maintaining vascular homeostasis therefore we assessed the contribution of endothelium to DHA and EPA mediated vasodilation.
Download: PPT. Fig 1. The effect of endothelium removal in n-3 PUFA-induced relaxation of rat arteries preconstricted with U Fig 2. Fig 3. The effect of clotrimazole in n-3 PUFA-induced relaxation of rat arteries preconstricted with U Role of K Ca channels in n-3 PUFA-dependent relaxation of rat mesenteric artery The EDH pathway is an integral component of endothelium-dependent relaxation in resistance arteries [ 32 ].
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Fig 5. Discussion CVDs are associated with the impairment of vasodilation mechanisms in arteries [ 14 , 37 ]. Conclusion The aim of this study was to characterise the mechanisms of DHA- and EPA-dependent vasodilation in rat conduit and resistance arteries. Fig 6. A schematic showing potential mechanisms involved in n-3 PUFA-induced relaxation of rat mesenteric artery and aorta preconstricted with U Supporting information.
S1 File. References 1. Prostacyclin increases cAMP in coronary arteries. J Cyclic Nucleotide Res. Prostacyclin and endothelium-dependent hyperpolarization. Pharmacol Rep. View Article Google Scholar 5. Cardiol Res Pract. View Article Google Scholar 6. Lim, A. Tan, J. Shimizu, J. Goto, I. Nishino, T. Toda, S. Morishita, S. Mao, C.
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