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

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

doi:10.1016/j.atherosclerosis.2009.06.014

« Previous Next »Atherosclerosis
Volume 208, Issue 1 , Pages 43-49, January 2010

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

Anita Racz
- Department of Pathophysiology, Semmelweis University, Budapest, Hungary
Zoltan Veresh
- Department of Pathophysiology, Semmelweis University, Budapest, Hungary
- Department of Physiology, New York Medical College, Valhalla, NY, USA
Gabor Lotz
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
Zsolt Bagi
- Department of Physiology, New York Medical College, Valhalla, NY, USA
Akos Koller
- Department of Pathophysiology, Semmelweis University, Budapest, Hungary
- Department of Physiology, New York Medical College, Valhalla, NY, USA
- Department of Pathophysiology and Gerontology, University of Pécs, Pécs, Hungary
- Corresponding author at: Department of Physiology, New York Medical College, Valhalla, NY 10595, USA. Tel.: +1 914 594 4085; fax: +1 914 594 4018.

Received 14 January 2009; received in revised form 2 June 2009; accepted 8 June 2009. published online 17 July 2009.

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: ∼250μm at 10mmHg) 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.

Keywords: HHcy, Venules, Flow-induced constriction, Thromboxane A₂, Cyclooxygenase-1 and 2, Oxidative stress