Altered cyclooxygenase-1 and enhanced thromboxane receptor activities underlie attenuated endothelial dilatory capacity of omental arteries in obesity

Abstract

Aims: Obesity is a risk factor for endothelial dysfunction, the severity of which is likely to vary depending on extent and impact of adiposity on the vasculature. This study investigates the roles of cyclooxygenase isoforms and thromboxane receptor activities in the differential endothelial dilatory capacities of arteries derived from omental and subcutaneous adipose tissues in obesity. Main methods: Small arteries were isolated from omental and subcutaneous adipose tissues obtained from consented morbidly obese patients (n=65, BMI 45±6 Kg.m-2 [Mean±SD]) undergoing bariatric surgery. Relaxation to acetylcholine was studied by wire myography in the absence or presence of indomethacin (10 µM, cyclooxygenase inhibitor), FR122047 (1 µM, cyclooxygenase-1 inhibitor), Celecoxib (4 µM, cyclooxygenase-2 inhibitor), Nω-Nitro-L-arginine methyl ester (L-Name, 100 µM, nitric oxide synthase inhibitor) or combination of apamin (0.5 µM) and charybdotoxin (0.1 µM) that together inhibit endothelium-derived hyperpolarizing factor (EDHF). Contractions to U46619 (thromboxane A2 mimetic) were also studied. Key findings: Acetylcholine relaxation was significantly attenuated in omental compared with subcutaneous arteries from same patients (p˂0.01). Indomethacin (p<0.01) and FR122047 (p<0.001) but not Celecoxib significantly improved the omental arteriolar relaxation. Cyclooxygenase-1 mRNA and U46619 contractions were both increased in omental compared with subcutaneous arteries (p˂0.05). L-Name comparably inhibited acetylcholine relaxation in both arteries, while apamin+charybdotoxin were less effective in omental compared with subcutaneous arteries. Significance: The results show that the depot-specific reduction in endothelial dilatory capacity of omental compared with subcutaneous arteries in obesity is in large part due to altered cyclooxygenase-1 and enhanced thromboxane receptor activities, which cause EDHF deficiency.

Downregulation of CYP17A1 By 20-hydroxyecdysone: Plasma Progesterone and Its Vasodilatory Properties

“…Tissues were collected immediately following euthanasia and were taken to the laboratory in normal physiological salt solution of the following composition: NaCl (112 mM), KCl (5 mM), CaCl 2 (1.8 mM), MgCl 2 (1 mM), NaHCO 3 (25 mM), KH 2 PO 3 (0.5 mM), NaH 2 PO 3 (0.5 mM) and glucose (10 mM) and gassed with 95% O 2 /5% CO 2 to pH 7.4. Segments (2 mm long) of the isolated arterioles were mounted in isometric myographs (510A; Danish Myo Technology A/S, Hinnerup, Denmark) and were pre-tensioned to an equivalent of 100 mm Hg using an automatic normalization protocol, which also determined the vessels’ luminal diameter as previously described [ 17 , 18 ]. The mounted segments were continuously aerated at 37°C and allowed an equilibration period of at least 1 h before experiments.…”

Endothelial cyclooxygenase-1 paradoxically drives local vasoconstriction and atherogenesis despite underpinning prostacyclin generation

“…Further, endogenous vascular cyclooxygenase pathways, which produce an array of vasoactive prostanoid mediators in addition to prostacyclin, typically provide vasoconstrictor rather than vasodilator tone. For example, cyclooxygenase-1 deletion/inhibition reduces constrictor responses in many isolated vessels including mouse aorta (4,10,(18)(19)(20), renal artery (11), carotid artery (20), femoral and mesenteric arteries (4) and human saphenous vein (21), omental arteries (22), and umbilical arteries (23). This complexity has also been observed in local vascular beds in vivo.…”

“…We next explored the impact of endothelial cyclooxygenase-1 knockout on the function of isolated vessels, analogous to previous work in the field that highlighted a potential vasoconstrictor role for vascular prostanoids (4,10,11,(18)(19)(20)(21)(22)(23). We focused on arteries from three vascular territories-descending aorta, carotid artery, and mesenteric artery-and first studied prostanoid production (measured as prostacyclin).…”

The renal microcirculation in chronic kidney disease: novel diagnostic methods and therapeutic perspectives

“…The endothelium is also injured in response to the damage of vascular homeostasis, which is causing by an increase in antiangiogenic factors, such as angiopoietin-2 (Ang-2) [ 20 ], and thromboxane A2 [ 21 ], and a decrease in proangiogenic factors, such as Ang-1 [ 22 , 23 ], vascular endothelial growth factor (VEGF), and EGF [ 24 ]. An imbalance in proangiogenic and antiangiogenic factors results in functional defects and structural abnormalities in microvessels.…”