Department of Pathophysiology, Semmelweis University, Budapest, Hungary.
Atherosclerosis. 2010 Jan;208(1):43-9. doi: 10.1016/j.atherosclerosis.2009.06.014. Epub 2009 Jun 18.
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.
Changes in diameter of isolated gracilis muscle venules (diameter: approximately 250 microm 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 A(2) (TxA(2)) 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.
In hyperhomocysteinemia increases in flow/shear stress increases the production of COX-2-derived TxA(2), 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.
高同型半胱氨酸血症（HHcy）已被证明会损害动脉血管的内皮功能并促进血栓形成。然而，目前尚无研究评估 HHcy 对小静脉血管舒缩功能的影响。我们假设 HHcy 激活了病理生理机制，损害了小静脉对血流/切应力依赖性反应。
测量对照和 HHcy 大鼠（用蛋氨酸饮食喂养 5 周诱导）的孤立比目鱼肌小静脉（直径：在 10mmHg 时约为 250 微米）的直径对腔内血流增加的反应。在对照大鼠中，血流增加引起血管扩张（最大时：14+/-1%），但在 HHcy 小静脉中引起血管收缩（最大时：-24+/-4%）。在存在血栓素 A2（TxA2）受体（TP）拮抗剂 SQ 29,548 的情况下，HHcy 小静脉中的血流诱导收缩转变为扩张，随后同时给予一氧化氮（NO）合酶抑制剂 L-NAME 和非选择性环氧化酶（COX）阻断剂吲哚美辛则消除了这种扩张。此外，选择性 COX-2 抑制剂 NS 398 将血流诱导的收缩转变为扩张，而 COX-1 抑制剂 SC 560 的额外添加则显著减少了这种扩张。此外，与对照组相比，HHcy 小静脉中检测到 SOD/CAT 敏感的溴化乙锭荧光增加，表明 HHcy 中产生了大量的活性氧（ROS）。相应地，SOD/CAT 减少了 HHcy 大鼠小静脉中血流诱导的收缩。
在高同型半胱氨酸血症中，血流/切应力的增加增加了 COX-2 衍生的 TxA2 和活性氧的产生，这些物质克服了 NO 和前列腺素的舒张作用，引起骨骼肌小静脉收缩；这些变化会增加血管阻力，有利于小静脉循环中的血栓形成。
