Veves A, Akbari C M, Primavera J, Donaghue V M, Zacharoulis D, Chrzan J S, DeGirolami U, LoGerfo F W, Freeman R
Department of Medicine, Microcirculation Lab, Beth Israel-Deaconess Medical Center, Boston, MA 02215, USA.
Diabetes. 1998 Mar;47(3):457-63. doi: 10.2337/diabetes.47.3.457.
We studied endothelial-mediated microvascular blood flow in neuropathic diabetic patients to determine the association between endothelial regulation of the microcirculation and the expression of endothelial constitutive nitric oxide synthetase (ecNOS) in the skin. Vasodilation on the dorsal foot in response to heating and iontophoresis of acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) were measured using single-point laser Doppler and laser Doppler imaging in diabetic patients with neuropathy (DN), with neuropathy and vascular disease (DI), with Charcot arthropathy (DA), and without complications (D), and in healthy control subjects (C). The response to heat was reduced in the DN (321 [21-629] percentage of increase over the baseline, median [interquartile range]) and DI (225 [122-470]) groups but was preserved in the DA (895 [359-1,229]), D (699 [466-1,029]), and C (810 [440-1,064], P < 0.0001) groups. The endothelial-mediated response to acetylcholine was reduced in the DN (17 [11-25]), DA (22 [2-34]), and DI (13 [2-30]) groups compared with the D (47 [24-58]) and C (44 [31-70], P < 0.001) groups. The non-endothelial-mediated response to sodium nitroprusside was also reduced in the DI (4 [0-18]), DN (17 [9-26]), and DA (21 [11-31]) groups compared with the D (37 [19-41]) and C (44 [26-67], P < 0.0001) groups. There was a significant reduction in vasodilation in the DI group compared with all other groups (P < 0.0001). Full thickness skin biopsies from the dorsum of the foot of 15 DN, 10 DI, and 11 C study subjects were immunostained with antiserum to human ecNOS, the functional endothelial marker GLUT1, and the anatomical endothelial marker von Willebrand factor. The staining intensity of ecNOS was reduced in both diabetic groups. No differences were found among the three groups in the staining intensity of von Willebrand factor and GLUT1. We conclude that the endothelium-dependent and endothelium-independent vasodilations are impaired in diabetic patients predisposed to foot ulceration and that neuropathy is the main factor associated with this abnormality. Reduced expression of ecNOS may be a major contributing factor for endothelial dysfunction. These data provide support for a close association of neuropathy and microcirculation in the pathogenesis of foot ulceration.
我们研究了神经性糖尿病患者内皮介导的微血管血流情况，以确定微循环的内皮调节与皮肤中内皮型一氧化氮合酶（ecNOS）表达之间的关联。使用单点激光多普勒和激光多普勒成像技术，测量了患有神经病变（DN）、伴有神经病变和血管疾病（DI）、患有夏科氏关节病（DA）以及无并发症（D）的糖尿病患者和健康对照者（C）足背对加热以及乙酰胆碱（内皮依赖性）和硝普钠（非内皮依赖性）离子导入的血管舒张反应。DN组（较基线增加的百分比为321[21 - 629]，中位数[四分位间距]）和DI组（225[122 - 470]）对热的反应降低，但DA组（895[359 - 1,229]）、D组（699[466 - 1,029]）和C组（810[440 - 1,064]，P < 0.0001）对热的反应得以保留。与D组（47[24 - 58]）和C组（44[31 - 70]，P < 0.001）相比，DN组（17[11 - 25]）、DA组（22[2 - 34]）和DI组（13[2 - 30]）对乙酰胆碱的内皮介导反应降低。与D组（37[19 - 41]）和C组（44[26 - 67]，P < 0.0001）相比，DI组（4[0 - 18]）、DN组（17[9 - 26]）和DA组（21[11 - 31]）对硝普钠的非内皮介导反应也降低。与所有其他组相比，DI组的血管舒张有显著降低（P < 0.0001）。对15名DN、10名DI和11名C研究对象足背的全层皮肤活检组织用抗人ecNOS抗血清、功能性内皮标志物GLUT1和解剖学内皮标志物血管性血友病因子进行免疫染色。两个糖尿病组中ecNOS的染色强度均降低。血管性血友病因子和GLUT1的染色强度在三组之间未发现差异。我们得出结论，在易发生足部溃疡的糖尿病患者中，内皮依赖性和非内皮依赖性血管舒张均受损，且神经病变是与这种异常相关的主要因素。ecNOS表达降低可能是内皮功能障碍的一个主要促成因素。这些数据为神经病变与微循环在足部溃疡发病机制中的密切关联提供了支持。
