Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration

被引:258
作者
Veves, A
Akbari, CM
Primavera, J
Donaghue, VM
Zacharoulis, D
Chrzan, JS
DeGirolami, U
LoGerfo, FW
Freeman, R
机构
[1] Beth Israel Deaconess Med Ctr, Microcirculat Lab, Boston, MA 02215 USA
[2] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA
[3] Beth Israel Deaconess Med Ctr, Dept Vasc Surg, Boston, MA 02215 USA
[4] Beth Israel Deaconess Med Ctr, Div Podiatry, Boston, MA 02215 USA
[5] Beth Israel Deaconess Med Ctr, Deaconess Joslin Foot Ctr, Boston, MA 02215 USA
[6] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA
[7] Childrens Hosp, Boston, MA 02115 USA
[8] Beth Israel Deaconess Med Ctr, Auton & Peripheral Nerve Lab, Dept Neurol, Boston, MA 02215 USA
[9] Harvard Univ, Sch Med, Boston, MA USA
关键词
D O I
10.2337/diabetes.47.3.457
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页码:457 / 463
页数:7
相关论文
共 36 条
[1]   THE EFFECT OF CHOLESTEROL-LOWERING AND ANTIOXIDANT THERAPY ON ENDOTHELIUM-DEPENDENT CORONARY VASOMOTION [J].
ANDERSON, TJ ;
MEREDITH, IT ;
YEUNG, AC ;
FREI, B ;
SELWYN, AP ;
GANZ, P .
NEW ENGLAND JOURNAL OF MEDICINE, 1995, 332 (08) :488-493
[2]  
[Anonymous], 1988, DIABETES, V37, P1000
[3]   VENOUS OXYGENATION IN THE DIABETIC NEUROPATHIC FOOT - EVIDENCE OF ARTERIOVENOUS SHUNTING [J].
BOULTON, AJM ;
SCARPELLO, JHB ;
WARD, JD .
DIABETOLOGIA, 1982, 22 (01) :6-8
[4]   ALBUMINURIA REFLECTS WIDESPREAD VASCULAR DAMAGE - THE STENO HYPOTHESIS [J].
DECKERT, T ;
FELDTRASMUSSEN, B ;
BORCHJOHNSEN, K ;
JENSEN, T ;
KOFOEDENEVOLDSEN, A .
DIABETOLOGIA, 1989, 32 (04) :219-226
[5]  
EBSKOV B, 1980, PROSTHET ORTHOT INT, V4, P77
[6]   BLOOD-FLOW IN THE DIABETIC NEUROPATHIC FOOT [J].
EDMONDS, ME ;
ROBERTS, VC ;
WATKINS, PJ .
DIABETOLOGIA, 1982, 22 (01) :9-15
[7]   DIABETIC NEUROPATHY AND THE MICROCIRCULATION [J].
FLYNN, MD ;
TOOKE, JE .
DIABETIC MEDICINE, 1995, 12 (04) :298-301
[8]  
FLYNN MD, DIABET MED, V8, P320
[9]  
FRYKBERG RG, 1995, MANAGEMENT DIABETIC, P88
[10]   EXPRESSION OF ENDOTHELIN-1 IN THE LUNGS OF PATIENTS WITH PULMONARY-HYPERTENSION [J].
GIAID, A ;
YANAGISAWA, M ;
LANGLEBEN, D ;
MICHEL, RP ;
LEVY, R ;
SHENNIB, H ;
KIMURA, S ;
MASAKI, T ;
DUGUID, WP ;
STEWART, DJ .
NEW ENGLAND JOURNAL OF MEDICINE, 1993, 328 (24) :1732-1739