Division of Hypertension and Vascular Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Am J Physiol Endocrinol Metab. 2011 Apr;300(4):E661-8. doi: 10.1152/ajpendo.00611.2010. Epub 2011 Jan 18.
Therapeutic angiogenesis remains unsuccessful in coronary artery disease. It is known that plasma endothelium-derived microparticles (EMPs) are increased in coronary artery disease and that hypercholesterolemia can inhibit angiogenesis. We evaluated the relationship between EMPs and hypercholesterolemia in the impairment of angiogenesis. EMPs isolated from human umbilical vein endothelial cells were injected into low-density lipoprotein receptor-null (LDLr(-/-)) mice fed a Western diet for 2 wk and C57BL6 mice for 6 h or were directly added to the tissue culture media. Hearts isolated from mice were sectioned and cultured, and endothelial tube formation was measured. The expression and phosphorylation of endothelial NO synthase (eNOS) and the generation of NO in the hearts were determined. Angiogenesis was inhibited by pathophysiological concentrations of EMPs but not physiological concentrations of EMPs in hearts from C57BL6 mice. However, angiogenesis was inhibited by EMPs at both physiological and pathophysiological concentrations of EMPs in hearts from hypercholesterolemic LDLr(-/-) mice. Pathophysiological concentrations of EMPs decreased eNOS phosphorylation at Ser(1177) and NO generation without altering eNOS expression in hearts from C57BL6 mice. Both physiological and pathophysiological concentrations of EMPs decreased not only eNOS phosphorylation at Ser(1177) and NO generation, but eNOS expression in hypercholesterolemic hearts from LDLr(-/-) mice. These data demonstrated that pathophysiological concentrations of EMPs could inhibit angiogenesis in hearts by decreasing eNOS activity. EMPs and hypercholesterolemia mutually enhanced their inhibitory effect of angiogenesis by inducing eNOS dysfunction. Our findings suggest a novel mechanism by which hypercholesterolemia impairs angiogenesis.
治疗性血管生成在冠状动脉疾病中仍然不成功。已知血浆内皮细胞衍生的微颗粒 (EMP) 在冠状动脉疾病中增加，并且高胆固醇血症可以抑制血管生成。我们评估了 EMP 与高胆固醇血症在血管生成损伤中的关系。从人脐静脉内皮细胞中分离出的 EMP 被注射到喂食西方饮食 2 周的低密度脂蛋白受体缺失 (LDLr(-/-)) 小鼠和 C57BL6 小鼠中，或直接添加到组织培养培养基中。分离小鼠的心脏并进行切片和培养，测量内皮管形成。测定心脏中内皮型一氧化氮合酶 (eNOS) 的表达和磷酸化以及 NO 的生成。生理浓度的 EMP 抑制了 C57BL6 小鼠心脏中的血管生成，但病理浓度的 EMP 则没有。然而，生理和病理浓度的 EMP 均抑制了高脂血症 LDLr(-/-) 小鼠心脏中的血管生成。病理浓度的 EMP 降低了 C57BL6 小鼠心脏中 eNOS 在 Ser(1177)的磷酸化和 NO 的生成，而不改变 eNOS 的表达。生理和病理浓度的 EMP 不仅降低了 Ser(1177)的 eNOS 磷酸化和 NO 的生成，而且降低了 LDLr(-/-)小鼠高脂血症心脏中的 eNOS 表达。这些数据表明，病理浓度的 EMP 可以通过降低 eNOS 活性来抑制心脏中的血管生成。EMP 和高胆固醇血症通过诱导 eNOS 功能障碍相互增强了它们对血管生成的抑制作用。我们的发现表明了一种新的机制，即高胆固醇血症损害血管生成。
