Oxidative stress and COX cause hyper‐responsiveness in vascular smooth muscle of the femoral artery from diabetic rats

Shi, Yi; Vanhoutte, PM

doi:10.1038/bjp.2008.110

Cited by 82 publications

(75 citation statements)

References 49 publications

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“…However, arterial remodeling and dysfunction of endothelial and smooth muscle cells are often present in the large conduit arteries in patients and animal models with hypertension. 10,11,13,16,17,37,49,50) Therefore, investigations of this artery may provide important information regarding the development of hypertension-associated vascular complications. Future research is needed to compare vascular function between large and small (resistance size) arteries in legs in the presence of hypertension.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms Underlying Enhanced Noradrenaline-Induced Femoral Arterial Contractions of Spontaneously Hypertensive Rats: Involvement of Endothelium-Derived Factors and Cyclooxygenase-Derived Prostanoids

Matsumoto

Watanabe

Iguchi

et al. 2016

Biological & Pharmaceutical Bulletin

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We investigated the relationship between noradrenaline (NAd)-induced contractions, endothelial function, and hypertension in femoral arteries isolated from spontaneously hypertensive rats (SHR). In the femoral arteries of SHR, vs. age-matched control Wistar Kyoto (WKY) rats, contractions induced by NAd were increased. These effects were enhanced by endothelial denudation, which abolished the differences between the two groups. NAd-induced contractions were enhanced by nitric oxide (NO) synthase inhibition, and further increased by the blockade of endothelium-derived hyperpolarizing factor (EDHF). Conversely, NAd-induced contractions were inhibited by cyclooxygenase (COX) inhibition. In addition, in SHR arteries, acetylcholine-induced relaxation was reduced, and components of endothelium-derived factors were altered, such as increased COX-derived vasoconstrictor prostanoids, reduced EDHF, and preserved NO-mediated relaxation. In the femoral arteries of SHR, the production of prostanoids [6-keto prostaglandin (PG)F 1α (a metabolite of prostacyclin (PGI 2 ), PGE 2 , and PGF 2α ] and COX-2 protein were increased compared with that in WKY rats. By contrast, contractions induced by beraprost (a stable PGI 2 analogue), PGE 2 , and U46619 (thromboxane/prostanoid receptor agonist) were similar between the SHR and WKY groups. Thus, NAdinduced femoral arterial contractions are augmented in SHR resulting from endothelial dysfunction and increased COX-derived vasoconstrictor prostanoid levels.Key words cyclooxygenase; endothelium; femoral artery; hypertension; contraction Hypertension is one of the most common chronic diseases in humans, 1) and hypertension-associated vascular complications such as stroke, heart failure, kidney diseases and peripheral arterial diseases are major sources of morbidity and mortality that exacerbate the quality of life.1-3) Because dysfunction and abnormal signaling in the main structural elements of the vasculature, such as endothelial cells and smooth muscle cells, are characteristic hypertension-associated vascular complications, [4][5][6][7][8][9] and functional impairments in these cells are observed in hypertensive patients and animal models of the disease, 10-19) a comprehensive understanding of the underlying mechanisms is indispensable for preventing and treating such complications.Among endothelium-derived factors, nitric oxide (NO) is of the greatest importance for modulating vascular function. 20,21) However, other factors including endothelium-derived hyperpolarizing factor (EDHF) and cyclooxygenase (COX)-derived prostanoids can also modulate vascular tone. [22][23][24][25] Indeed, there are several reports suggesting that contraction induced by various substances including alpha-adrenoceptor ligands is enhanced by the inhibition of EDHF signaling 26) and enhanced 27) or suppressed 11,28,29) by COX signaling in various arteries under a (patho) physiological state. Because prostacyclin (PGI 2 ) serves as an endothelium-derived vasodilator and vasoconstrictor depending on the vessel t...

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Section: Discussionmentioning

confidence: 99%

Mechanisms Underlying Enhanced Noradrenaline-Induced Femoral Arterial Contractions of Spontaneously Hypertensive Rats: Involvement of Endothelium-Derived Factors and Cyclooxygenase-Derived Prostanoids

Matsumoto

Watanabe

Iguchi

et al. 2016

Biological & Pharmaceutical Bulletin

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“…On the other hand, COX-1-derived PGI 2 has been found to mediate endothelium-derived vasoconstrictor activity or to increase the stiffness of resistance arteries in a rat or mouse model of hypertension, respectively (10,44). Also, there are studies indicating that COX-1 can also be upregulated, and, in some diabetic arteries, inhibition of COX-1 abolishes endothelium-dependent contraction evoked by a Ca 2ϩ ionophore (8,36,37). We speculate that in the given diabetic arteries, COX-1 may remain as a major COX form, mediating endothelial PGI 2 synthesis to evoke vasoconstrictor activity under the pathological condition.…”

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confidence: 99%

Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in non-insulin-dependent diabetic mice induced by high-fat diet and streptozotocin

Zhu

Liu

Luo

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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. Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in noninsulin-dependent diabetic mice induced by high-fat diet and streptozotocin. Am J Physiol Heart Circ Physiol 307: H319 -H327, 2014. First published May 30, 2014 doi:10.1152/ajpheart.00022.2014.-This study tested the hypothesis that in diabetic arteries, cyclooxygenase (COX)-1 mediates endothelial prostacyclin (PGI2) synthesis, which evokes vasoconstrictor activity under the pathological condition. Non-insulin-dependent diabetes was induced to C57BL/6 mice and those with COX-1 deficiency (COX-1 Ϫ/Ϫ mice) using a high-fat diet in combination with streptozotocin injection. In vitro analyses were performed 3 mo after. Results showed that in diabetic aortas, the endothelial muscarinic receptor agonist ACh evoked an endothelium-dependent production of the PGI2 metabolite 6-keto-PGF1␣, which was abolished in COX-1 Ϫ/Ϫ mice. Meanwhile, COX-1 deficiency or COX-1 inhibition prevented vasoconstrictor activity in diabetic abdominal aortas, resulting in enhanced relaxation evoked by ACh. In a similar manner, COX-1 deficiency increased the relaxation evoked by ACh in nitric oxide synthase-inhibited diabetic renal arteries. Also, in diabetic abdominal aortas and/or renal arteries, both PGI2 and the COX substrate arachidonic acid evoked contractions similar to those of nondiabetic mice. However, the contraction to arachidonic acid, but not that to PGI2, was abolished in vessels from COX-1 Ϫ/Ϫ mice. Moreover, we found that 3 mo after streptozotocin injection, systemic blood pressure increased in diabetic C57BL/6 mice but not in diabetic COX-1 Ϫ/Ϫ mice. These results explicitly demonstrate that in the given arteries from non-insulin-dependent diabetic mice, COX-1 remains a major contributor to the endothelial PGI2 synthesis that evokes vasoconstrictor activity under the pathological condition. Also, our data suggest that COX-1 deficiency prevents or attenuates diabetic hypertension in mice, although this could be related to the loss of COX-1-mediated activities derived from both vascular and nonvascular tissues. diabetes; arachidonic acid; metabolism; thromboxane prostanoid receptors; contraction CYCLOOXYGENASE (COX

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“…In the rat also, chronic exposure to high arterial blood pressure, diabetes mellitus, and oxidative stress can cause upregulation of COX in vascular smooth muscle. 8,9 Again, being utterly critical when looking at the immunostaining images provided, 1 one could argue that the integrity of the endothelial cell layer in the arteries from their hypertensive patients is not as well preserved as in the preparations of their normotensive subjects and thus that the suggestion of a decreased endothelial expression of COX can be questioned. Nevertheless, giving them the benefit of the doubt, if the problem with the chronic exposure to high blood pressure is mainly the abundance in the media of COX generating ROS, the unavoidable conclusion is that the release of NO is just fine (as suggested by the normal responses to acetylcholine in the presence of either ascorbic acid or apocynin plus the COX-2 inhibitor) in the small arteries of the hypertensive patients; again, a similar conclusion had been reached in the SHR aorta when NO was called EDRF…”

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confidence: 99%

One or Two, Does it Matter as Long as the Arterial Wall Is Coxygenated?

Vanhoutte

2013

Hypertension

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http://hyper.ahajournals.org/ Downloaded from Vanhoutte COX Products Reduce Endothelium-Dependent Relaxations 245(endothelium-derived relaxing factor). 10 In addition, Virdis et al 1 report that substantial relaxations to acetylcholine remain in the presence of L-NAME (Nω-nitro-L-arginine methyl ester) (with or without COX inhibitors), although they do not comment further on the mechanism underlying them. In the absence of sympathetic nerve activity under their in vitro experimental conditions (which they amusingly term clinical setting), these L-NAME-resistant relaxations to acetylcholine can reasonably be attributed to endothelium-dependent hyperpolarization. They are remarkably similar in preparations of normotensive and essential hypertensive subjects.1 Hence, is the endothelium of the latter truly dysfunctional or is it trying very hard to cope with the abnormal events in the media?At first sight, the situation in the hypertensive humans, with medial COX-2-generating superoxide anions that scavenge endothelium-derived NO, seems to differ fundamentally from that in the SHR, the most commonly used animal model of essential hypertension. Indeed, in the latter endothelial COX-1 can be upregulated and seems to play a dominant role in endothelium-dependent responses by generating vasoconstrictor prostaglandins but also ROS. 4,5,8 However, does it really matter whether COX-1 or COX-2 are upregulated and whether the upregulation is in the endothelium or the media? Indeed, the consequences seem to be the same, and the common result is abnormal endothelium-dependent relaxation to acetylcholine, an accepted biomarker of increased risk for vascular disease (Figure). Is the important question not why do we see upregulation of COX (whether COX-1 or COX-2) in the vascular wall (whether intima or media) of chronically hypertensive mammals? What feedback loop is dysregulated to the extent that such excessive production of ROS and vasoconstrictor prostanoids is permitted? If one takes the simple-minded approach that production of prostaglandins is the primary role of COX, this implies that any regulatory feedback loop must involve the end products of the enzyme. Then, one can only speculate, in the absence of overt signs of local inflammation, that the COX overexpression after chronic exposure to high blood pressure results from an imbalance in prostanoid receptor responsiveness/sensitivity in either endothelial (SHR) or vascular smooth muscle (essential hypertensive human) cells preventing end product feedback inhibition.The unequivocal message given by the tissues studied by Virdis et al 1 is that, at least in small arteries of subcutaneous fat of hypertensive subjects, COX-2, a usual suspect in pathology, is indeed the major culprit in causing abnormal endothelium-dependent relaxations to acetylcholine. Their findings throw a new light on the vascular, possibly beneficial effects of COX-2 inhibition. Whether or not, after the rofecoxib tsunami, their enthusiasm will be sufficient to reactivate interest in the pharmaceutic...

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Oxidative stress and COX cause hyper‐responsiveness in vascular smooth muscle of the femoral artery from diabetic rats

Cited by 82 publications

References 49 publications

Mechanisms Underlying Enhanced Noradrenaline-Induced Femoral Arterial Contractions of Spontaneously Hypertensive Rats: Involvement of Endothelium-Derived Factors and Cyclooxygenase-Derived Prostanoids

Mechanisms Underlying Enhanced Noradrenaline-Induced Femoral Arterial Contractions of Spontaneously Hypertensive Rats: Involvement of Endothelium-Derived Factors and Cyclooxygenase-Derived Prostanoids

Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in non-insulin-dependent diabetic mice induced by high-fat diet and streptozotocin

One or Two, Does it Matter as Long as the Arterial Wall Is Coxygenated?

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