Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Nov 2:1:145.
doi: 10.3389/fphys.2010.00145. eCollection 2010.

Cyclooxygenase-2 inhibition restored endothelium-mediated relaxation in old obese zucker rat mesenteric arteries

Emilie Vessières  1 , Eric J Belin de Chantemèle, Bertrand Toutain, Anne-Laure Guihot, Alain Jardel, Laurent Loufrani, Daniel Henrion
Affiliations

Cyclooxygenase-2 inhibition restored endothelium-mediated relaxation in old obese zucker rat mesenteric arteries

Emilie Vessières et al. Front Physiol. .

Abstract

Metabolic syndrome is associated with reduced endothelial vasodilator function. It is also associated with the induction of cyclooxygenase-2 (COX2), which produces vasoactive prostanoids. The frequency of metabolic syndrome increases with age and aging per se is a risk factor associated with reduced endothelium-mediated relaxation. Nevertheless, the combined effect of aging and metabolic syndrome on the endothelium is less known. We hypothesized that COX2 derived prostanoids may affect endothelium function in metabolic syndrome associated with aging. We used obese Zucker rats, a model of metabolic syndrome. First order mesenteric arteries were isolated from 4- and 12-month-old rats and acetylcholine (endothelium)-dependent relaxation determined using wire-myography. Endothelium-mediated relaxation, impaired in young Zucker rats (89 versus 77% maximal relaxation; lean versus Zucker), was further reduced in old Zucker rats (72 versus 51%, lean versus Zucker). The effect of the nitric oxide-synthesis inhibitor L-NAME on the relaxation was reduced in both young and old Zucker rats without change in eNOS expression level. COX inhibition (indomethacin) improved acetylcholine-mediated relaxation in old obese rats only, suggesting involvement of vasoconstrictor prostanoids. In addition, COX2 inhibition (NS398) and TxA2/PGH2 receptor blockade (SQ29548) both improved relaxation in old Zucker rat arteries. Old Zucker rats had the highest TxB2 (TxA2 metabolite) blood level associated with increased COX2 immunostaining. Chronic COX2 blockade (Celecoxib, 3 weeks) restored endothelium-dependent relaxation in old Zucker rats to the level observed in old lean rats. Thus the combination of aging and metabolic syndrome further impairs endothelium-dependent relaxation by inducing an excessive production of COX2-derived vasoconstrictor(s); possibly TxA2.

Keywords: aging; cyclooxygenase-2; endothelium; metabolic syndrome; resistance arteries; vasodilatation.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Acetylcholine-mediated relaxation in mesenteric resistance arteries isolated from young (A) or old (B) lean and obese Zucker rats. Concentration–response curves to acetylcholine were repeated after incubation with L-NAME (LN) and then with L-NAME plus indomethacin (LN + indo). Bargraphs (C) represent the maximal relaxation obtained in each group (taken from A and B). (D) Precontraction applied to the arteries before adding acetylcholine. (E) eNOS and β-actin expression level determined using Western blot. Mean ± SEM is presented (n = 8 per group). *P < 0.01, old versus young rats. #P < 0.01, obese versus lean rats. $P < 0.01, indo versus LN.
Figure 2
Figure 2
Sodium nitroprusside-mediated relaxation in mesenteric arteries isolated from lean and obese Zucker rats aged 3 (young) or 12 months (old). (A). Luminal diameter, media cross-section, and media/lumen ratio are shown in (B–D) respectively. Mean ± SEM is presented (n = 8 per group). *P < 0.01, old versus young rats. #P < 0.01, obese versus lean rats.
Figure 3
Figure 3
Effect of COX2 inhibition with NS398 (A) or TxA2/PGH2 receptor blockade with SQ29548 (B) on acetylcholine-mediated relaxation in mesenteric resistance arteries isolated from young (A) or old (B) lean and obese Zucker rats. Mean ± SEM is presented (n = 8 per group). *P < 0.01, effect of NS398 (A) or SQ29548 (B).
Figure 4
Figure 4
Plasma TxB2 (A), 6-keto-PGF1alpha (B), 8-isoprostane (C) in 3- and 12-month-old lean or obese Zucker rats. Rats were treated with the COX2 inhibitor Celecoxib (Cel) or its solvent (Solv). Mean ± SEM is presented (n = 8 per group). *P < 0.01, obese versus lean rats. #P < 0.01, Celecoxib versus solvent.
Figure 5
Figure 5
(A) Detection of COX2 in mesenteric resistance arteries isolated from young or old lean and obese Zucker rats using immunostaining and confocal microscopy. A negative control was obtained by omitting the primary antibody (Neg. control) and a positive control was obtained using arteries from a lipopolysaccharide-treated rat (Pos. control). Quantification of the positive labeling is shown in the upper bargraph. (B) Quantitation of COX2 and β-actin using Western blot. Mean ± SEM is presented (n = 8 per group). *P < 0.01, old versus young rats. #P < 0.01, obese versus lean rats.
Figure 6
Figure 6
Acetylcholine-mediated relaxation in mesenteric resistance arteries isolated from or old lean and obese Zucker rats (A). Rats were treated chronically with the COX2 inhibitor Celecoxib or its solvent. Mean ± SEM is presented (n = 8 per group). Acetylcholine-mediated relaxation was repeated in the presence of L-NAME (LN), L-NAME plus indomethacin (indo), or SQ29548 (SQ) and the effect is shown in the bargraph (B). *P < 0.01, effect of the chronic treatment with Celecoxib. #P < 0.001, effect of L-NAME.
See this image and copyright information in PMC

References

    1. Arkin J. M., Alsdorf R., Bigornia S., Palmisano J., Beal R., Istfan N., Hess D., Apovian C. M., Gokce N. (2008). Relation of cumulative weight burden to vascular endothelial dysfunction in obesity. Am. J. Cardiol. 101, 98–10110.1016/j.amjcard.2007.07.055 - DOI - PMC - PubMed
    1. Bagi Z., Erdei N., Toth A., Li W., Hintze T. H., Koller A., Kaley G. (2005). Type 2 diabetic mice have increased arteriolar tone and blood pressure: enhanced release of COX-2-derived constrictor prostaglandins. Arterioscler. Thromb. Vasc. Biol. 25, 1610–161610.1161/01.ATV.0000172688.26838.9f - DOI - PubMed
    1. Belin de Chantemele E. J., Vessieres E., Guihot A. L., Toutain B., Loufrani L., Henrion D. (2010). Cyclooxygenase-2 preserves flow-mediated remodelling in old obese Zucker rat mesenteric arteries. Cardiovasc. Res. 86, 516–52510.1093/cvr/cvp411 - DOI - PubMed
    1. Belin de Chantemele E. J., Vessieres E., Guihot A. L., Toutain B., Maquignau M., Loufrani L., Henrion D. (2009). Type 2 diabetes severely impairs structural and functional adaptation of rat resistance arteries to chronic changes in blood flow. Cardiovasc. Res. 81, 788–79610.1093/cvr/cvn334 - DOI - PubMed
    1. Ben Driss A., Devaux C., Henrion D., Duriez M., Thuillez C., Levy B. I., Michel J. B. (2000). Hemodynamic stresses induce endothelial dysfunction and remodeling of pulmonary artery in experimental compensated heart failure. Circulation 101, 2764–2770 - PubMed