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

Abstract

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.

The role of nitric oxide synthase isoforms and arginase in the pathogenesis of diabetic foot ulcers: possible modulatory effects by transforming growth factor beta 1

“…It was suggested that this could be a contributing factor to the endothelial cell dysfunction observed in diabetic patients. We have confirmed the finding that diabetic patients have lower ecNOS than control subjects, however, in another study [24], the activity of ec-NOS at the site of ulceration was not determined. We have therefore extended these observations by showing raised ecNOS and iNOS in DFU patients.…”

“…It would, however, be difficult to obtain samples to determine NOS activity in non-treated diabetic patients. It has recently been shown that ecNOS immunoreactivity in the skin of diabetic neuropathic patients and diabetic patients with neuropathy and vascular disease are reduced compared with control subjects [24]. It was suggested that this could be a contributing factor to the endothelial cell dysfunction observed in diabetic patients.…”

Corneal confocal microscopy detects severe small fiber neuropathy in diabetic patients with Charcot neuroarthropathy

“…Previous studies have assessed small fiber dysfunction indirectly by assessing abnormalities in skin blood flow, and although some have shown an abnormality18, others have not17, 33. In the present study, we have shown widespread small fiber damage with a marked loss of corneal nerve fibers and sudomotor dysfunction in both the hands and feet of patients with CN compared to patients with type 2 diabetes.…”

“…Indeed, there is a substantial literature on the role of non‐synaptically released substance P and CGRP, regulating osteoblast and osteoclast proliferation15, and inhibiting pro‐inflammatory cytokines16, key players in the pathophysiology of CN. Whereas in a study of 23 patients with CN, small fiber integrity, assessed by the hyperemic response to heating skin, was found to be preserved17, a subsequent study from the same group showed an impaired nerve–axon reflex in patients with CN18. More direct bone biopsy studies have shown reduced expression of CGRP in the bone of patients with CN compared to patients with diabetic neuropathy only19.…”

The ratio of observed to predicted left ventricular mass is independently associated with increased cardiovascular events in patients with chronic kidney disease

“…[1][2][3][4] A number of hemodynamic and metabolic disturbances affect the structure and function of the heart in patients with CKD. 5 To compensate for the hemodynamic and metabolic alterations, an excessive increase in the left ventricular mass (LVM), a condition that has been termed 'inappropriate LVM' , is frequently found in patients with CKD. 6 The predicted LVM based on sex, height 2,7 and hemodynamic load can be used as an appropriate reference for the observed LVM.…”