Cyclooxygenase-2 derived thromboxane A2 and reactive oxygen species mediate flow-induced constrictions of venules in hyperhomocysteinemia

Anita Racz, Zoltan Veresh, Gabor Lotz, Zsolt Bagi, Akos Koller

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Objective: Hyperhomocysteinemia (HHcy) has been shown to impair the endothelial function of arterial vessels and promote thrombosis. There are no studies, however, assessing the effects of HHcy on the vasomotor function of venules. We hypothesized that HHcy activates pathophysiological mechanisms impairing flow/shear stress-dependent responses of venules. Methods and results: Changes in diameter of isolated gracilis muscle venules (diameter: ∼250 μm at 10 mmHg) of control and HHcy rats (induced by methionine diet for 5 weeks) to increases in intraluminal flow were measured. Increases in flow elicited dilations in control (at max.: 14 ± 1%), but induced constrictions in HHcy venules (at max.: -24 ± 4%). Flow-induced constrictions in HHcy venules were converted to dilations in the presence of the thromboxane A2 (TxA2) receptor (TP) antagonist SQ 29,548, which were then abolished by the simultaneous administration of nitric oxide (NO) synthase inhibitor, L-NAME and non-selective cyclooxygenase (COX) blocker, indomethacin. In addition, the selective COX-2 inhibitor NS 398 reversed flow-induced constrictions to dilations, which were significantly decreased by additional COX-1 inhibitor, SC 560. Also, as compared to controls, a SOD/CAT sensitive increased ethidium bromide fluorescence was detected in HHcy small veins, indicating substantial production of reactive oxygen species (ROS) in HHcy. Correspondingly, SOD/CAT diminished flow-induced constrictions in venules of HHcy rats. Conclusions: In hyperhomocysteinemia increases in flow/shear stress increases the production of COX-2-derived TxA2, and reactive oxygen species - that overcome the dilator effects of NO and prostaglandins - eliciting constrictions in skeletal muscle venules; changes which can increase vascular resistance and favor thrombus formation in the venular circulation.

Original languageEnglish (US)
Pages (from-to)43-49
Number of pages7
JournalAtherosclerosis
Volume208
Issue number1
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

Keywords

  • Cyclooxygenase-1 and 2
  • Flow-induced constriction
  • HHcy
  • Oxidative stress
  • Thromboxane A
  • Venules

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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