Intraluminal pressure modulates eicosanoid enzyme expression in vascular endothelium of intact human conduit vessels at physiological levels of shear stress

Doroudi, Roya; Gan, Li‐Ming; Sjögren, Lena Selin; Jern, Sverker

doi:10.1097/00004872-200201000-00010

Cited by 5 publications

(6 citation statements)

References 21 publications

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“…Alternatively, because testosterone exposure occurred in vivo, we cannot rule out indirect effects that could modulate the levels of TxA 2 synthase. For example, changes in shear stress were recently shown in human umbilical veins to affect TxA 2 expression; however, unlike testosterone exposure, prostacyclin synthase was also upregulated by shear (11). While the mechanisms remain to be elucidated, an effect on TxA 2 synthase is consistent with an earlier observation that monkeys treated with testosterone exhibit elevated plasma levels of TxA 2 (45).…”

Section: Discussionsupporting

confidence: 79%

Testosterone treatment increases thromboxane function in rat cerebral arteries

Gonzales¹,

Ghaffari²,

Duckles³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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We previously showed that testosterone, administered in vivo, increases the tone of cerebral arteries. A possible underlying mechanism is increased vasoconstriction through the thromboxane A2 (TxA2) pathway. Therefore, we investigated the effect of chronic testosterone treatment (4 wk) on TxA2 synthase levels and the contribution of TxA2 to vascular tone in rat middle cerebral arteries (MCAs). Using immunofluorescence and confocal microscopy, we demonstrated that TxA2 synthase is present in MCA segments in both smooth muscle and endothelial layers. Using Western blot analysis, we found that TxA 2 synthase protein levels are higher in cerebral vessel homogenates from testosteronetreated orchiectomized (ORXϩT) rats compared with orchiectomized (ORX) control animals. Functional consequences of changes in cerebrovascular TxA2 synthase were determined using cannulated, pressurized MCA segments in vitro. Constrictor responses to the TxA2 mimetic U-46619 were not different between the ORXϩT and ORX groups. However, dilator responses to either the selective TxA 2 synthase inhibitor furegrelate or the TxA2-endoperoxide receptor (TP) antagonist SQ-29548 were greater in the ORXϩT compared with ORX group. In endothelium-denuded arteries, the dilation to furegrelate was attenuated in both the ORX and ORXϩT groups, and the difference between the groups was abolished. These data suggest that chronic testosterone treatment enhances TxA 2-mediated tone in rat cerebral arteries by increasing endothelial TxA 2 synthesis without altering the TP receptors mediating constriction. The effect of in vivo testosterone on cerebrovascular TxA 2 synthase, observed here after chronic hormone administration, may contribute to the risk of vasospasm and thrombosis related to cerebrovascular disease. thromboxane synthase; cerebral circulation; vascular smooth muscle; endothelium ALTHOUGH THE RISK for cardiovascular disease and stroke is higher in males, the influence of testosterone on vascular function is not well understood (25). This lack of information also fuels concerns about the vascular impact of testosterone therapy for elderly men (33) and postmenopausal women (28) as well as the use of anabolic androgens in young athletes, both male and female (30). Androgens appear to influence a variety of cardiovascular risk factors including lipid profile, platelet aggregation, blood pressure, and vascular reactivity (1,25,31,44). Data on vascular reactivity, however, are limited and often conflicting. For example, acute exposure of arteries to testosterone has been found to cause either vasodilation or vasoconstriction (6,7,25,40,43), whereas chronic testosterone exposure in vivo results in increased vascular tone (13)(14)(15)31). A better understanding of how testosterone modulates vascular function is needed to explain these observations. In the cerebral circulation, the critical vascular bed in stroke, arterial tone is elevated after in vivo treatment with testosterone (14, 15, 31). Using rat middle cerebral arteries (MCAs), we demonstrated th...

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Section: Discussionsupporting

confidence: 79%

Testosterone treatment increases thromboxane function in rat cerebral arteries

Gonzales¹,

Ghaffari²,

Duckles³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…2C and D). It has been reported that not only COX-2, but also COX-1 is induced in the vessel walls, either by the increased fluid shear stress or increased intraluminal pressure [11,12], although COX-1 is generally expressed constitutively. To examine the possibility whether shear stress or increased luminal pressure of the heart vessels was involved in the hypergravity-dependent COX-2 induction, we determined expression of COX-1 in the heart by immunohistochemistry.…”

Section: Resultsmentioning

confidence: 99%

“…3). Induction of both COX enzymes in the vessel walls strongly suggest that shear stress or increased inner pressure of -10-the vessels stimulates COX-2 expression [11,12]. It is possible that hemodynamic changes under hypergravity increased blood volume in the heart vessels, causing shear stress and increased pressure.…”

Section: Resultsmentioning

confidence: 99%

“…For example, increased inner pressure in the bladder and glomeruli induce COX-2 expression in the bladder detrusor -4-muscle and glomerular podocytes, respectively [8,9]. Moreover, fluid shear stress and increased luminal pressure of vessels induce expression of COX-2 in the vessel walls [10][11][12]. Accordingly, it is possible that mechanical stimuli caused by gravitational force stimulate COX-2 expression in other tissues than bone, and affect their physiological functions.…”

Section: Introductionmentioning

confidence: 99%

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Hypergravity induces expression of cyclooxygenase-2 in the heart vessels

Oshima

Taketo

2005

Biochemical and Biophysical Research Communications

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Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin biosynthesis, is induced by various stimuli including mechanical stress and plays important roles in pathophysiological conditions. For example, gravitational stress has been shown to induce expression of COX-2 in bone tissues, which is essential for bone homeostasis. To investigate whether COX-2 is induced by gravitational loading in other tissues than bone, we exposed mice to hypergravity at 2G and 3G for 4 h. We demonstrate here that COX-2 is induced in the mouse heart vessels by hypergravity. Moreover, hypoxia-inducible factor (HIF)-1alpha and its downstream genes such as inducible nitric oxide synthase, vascular endothelial growth factor, and heme oxygenase-1 were induced in the heart simultaneously, while none of these genes were induced in the COX-2(-/-) mouse heart. Therefore, COX-2 induced in the heart helps protect the heart function against hypoxia under hypergravity condition through HIF-1alpha induction.

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“…[27][28][29][30][31] Expression of COX-2 and biosynthesis of PGI 2 are upregulated by elevation of shear stress, a key regulator of vascular homeostasis. [32][33][34] COX-2 is a major source of PGI 2 in humans and a potent endogenous vasodilator and anti-atherogenic molecule. 32,35 PGI 2 prevents platelet aggregation, inhibits smooth muscle proliferation, and stimulates angiogenesis.…”

Section: Experimental Groupsmentioning

confidence: 99%

Endothelial Progenitor Cells Stimulate Cerebrovascular Production of Prostacyclin By Paracrine Activation of Cyclooxygenase-2

Santhanam

Smith

et al. 2007

Circulation Research

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Abstract-In the present study we hypothesized that endothelial progenitor cells (EPCs) enhance production of vasoprotective substances in cerebral arteries. Isolated mononuclear cells from rabbit peripheral blood were cultured in endothelial growth medium (EGM-2) for 7 days to yield EPCs. Rabbit basilar arteries were exposed to autologous EPCs (Ϸ5ϫ10 5 cells) in vitro or in vivo. Twenty-four hours after intracisternal delivery of autologous EPCs, basilar arteries were isolated and expression of vasoregulatory proteins, production of prostacyclin (PGI 2 ), and cAMP were determined. Arteries transplanted with EPCs demonstrated increased protein expression of cyclooxygenase-2 and PGI 2 in adventitia, media, and endothelium. Furthermore, production of PGI 2 and arterial content of cAMP, second messenger for PGI 2 , were significantly augmented after transplantation of EPCs. In contrast, production of thromboxane A 2 was significantly reduced, whereas production of prostaglandin E 2 remained unchanged. The increased production of PGI 2 and arterial content of cAMP were inhibited only by a selective cyclooxygenase-2 inhibitor, NS-398. In vitro or in vivo treatment of basilar artery with conditioned media from EPCs also caused increase in cyclooxygenase-2 and PGI 2 synthase protein expression associated with elevation of cAMP. Our results suggest that in cerebral arteries, paracrine effect of EPCs promotes vasoprotection by increasing PGI 2 production and intracellular concentration of cAMP. This effect appears to be mediated by activation of arachidonic acid metabolism via stimulation of cyclooxygenase-2/PGI 2 synthase pathway.

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Intraluminal pressure modulates eicosanoid enzyme expression in vascular endothelium of intact human conduit vessels at physiological levels of shear stress

Cited by 5 publications

References 21 publications

Testosterone treatment increases thromboxane function in rat cerebral arteries

Testosterone treatment increases thromboxane function in rat cerebral arteries

Hypergravity induces expression of cyclooxygenase-2 in the heart vessels

Endothelial Progenitor Cells Stimulate Cerebrovascular Production of Prostacyclin By Paracrine Activation of Cyclooxygenase-2

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