Xu X, Li J, Simons M, Li J, Laham R J, Sellke F W
Harvard Medical School and the Division of Cardiothoracic Surgery and Angiogenesis Research Center, Beth Israel Deaconess Medical Center, 110 Francis St., Boston, MA 02215, USA.
J Thorac Cardiovasc Surg. 2001 Apr;121(4):735-42. doi: 10.1067/mtc.2001.112340.
Vascular endothelial growth factor, a specific endothelial mitogen, plays an important role in myocardial angiogenesis. Previous work has demonstrated increased expression of vascular endothelial growth factor and its receptors in a rat myocardial infarction model, as well as in a pig model of chronic ischemia. The expression of vascular endothelial growth factor and other growth factors after acute myocardial ischemia in patients has not been examined. In this study we examined the expression of vascular endothelial growth factor and its receptors and the responsiveness of human atrial microvessels to vascular endothelial growth factor before and after acute ischemia.
Paired specimens of human atrial tissue were harvested before and after atrial devascularization (ligation) in 16 patients undergoing coronary bypass operations.
The messenger RNA (reverse transcriptase-polymerase chain reaction) level of vascular endothelial growth factor and vascular endothelial growth factor receptor 1 were increased by 22.2% +/- 4.2% and 30.7% +/- 7.6%, respectively (P <.05), in the ischemic specimens as compared with the control specimens. Protein expression (Western blotting) of vascular endothelial growth factor and that of vascular endothelial growth factor receptor 1 also were increased significantly by 71.7% +/- 27.8% and 68.2% +/- 27.6%, respectively (P <.05). However, both RNA and protein expressions of another vascular endothelial growth factor receptor, vascular endothelial growth factor receptor 2, and fibroblast growth factor and fibroblast growth factor receptor 1 were unchanged. Reactivity of precontracted atrial vessels was examined with video microscopy. Vascular endothelial growth factor-induced (33.9% +/- 2.4% vs 18.3% +/- 2.8% in control and ischemic vessels, respectively; P <.05), fibroblast growth factor-induced (31.6% +/- 3.2% vs 15.8% +/- 4.1%, P <.05), and substance P-induced (84.5% +/- 3.7% vs 54.3% +/- 9.0%, P <.05) microvascular relaxations were decreased in ischemic samples and in the presence of N (G)nitro-L -arginine, whereas responses to sodium nitroprusside were unchanged (90.9% +/- 2.2% vs 91.2% +/- 2.0%).
This study suggests that acute myocardial ischemia in patients results in increased expression of vascular endothelial growth factor but not fibroblast growth factor and that the functional activity of vascular endothelial growth factor receptors and that of other growth factors may be impaired.
血管内皮生长因子是一种特异性内皮细胞有丝分裂原，在心肌血管生成中起重要作用。先前的研究已证实在大鼠心肌梗死模型以及猪慢性缺血模型中血管内皮生长因子及其受体的表达增加。但尚未对急性心肌缺血患者体内血管内皮生长因子及其他生长因子的表达进行研究。在本研究中，我们检测了急性缺血前后人心房微血管中血管内皮生长因子及其受体的表达以及人心房微血管对血管内皮生长因子的反应性。
在16例行冠状动脉搭桥手术的患者中，于心房去血管化（结扎）前后获取配对的人心房组织标本。
与对照标本相比，缺血标本中血管内皮生长因子的信使核糖核酸（逆转录聚合酶链反应）水平及血管内皮生长因子受体1分别升高了22.2%±4.2%和30.7%±7.6%（P<.05）。血管内皮生长因子及血管内皮生长因子受体1的蛋白表达（蛋白质印迹法）也分别显著升高了71.7%±27.8%和68.2%±27.6%（P<.05）。然而，另一种血管内皮生长因子受体血管内皮生长因子受体2以及成纤维细胞生长因子和成纤维细胞生长因子受体1的核糖核酸和蛋白表达均未改变。采用视频显微镜检查预收缩心房血管的反应性。血管内皮生长因子诱导的舒张（对照血管和缺血血管分别为33.9%±2.4%和18.3%±2.8%；P<.05）、成纤维细胞生长因子诱导的舒张（31.6%±3.2%对15.8%±4.1%，P<.05）以及P物质诱导的舒张（84.5%±3.7%对54.3%±9.0%，P<.05）在缺血标本及存在N（G）硝基-L-精氨酸时均降低，而对硝普钠的反应未改变（90.9%±2.2%对91.2%±2.0%）。
本研究提示，患者急性心肌缺血导致血管内皮生长因子表达增加而成纤维细胞生长因子表达未增加，且血管内皮生长因子受体及其他生长因子的功能活性可能受损。
