Endoneurial Microvessels in Human Diabetic Neuropathy: Endothelial Cell Dysjunction and Lack of Treatment Effect by Aldose Reductase Inhibitor

Abstract

Endoneurial microvascular abnormalities have been invoked in the pathogenesis of diabetic distal symmetric polyneuropathy. Detailed morphometric analysis of the endoneurial microvasculature was correlated with previously published data on nerve fiber morphometry and teased fiber analysis obtained from the same sural nerve biopsies. Biopsy specimens from neuropathic diabetic patients were obtained before and after 12 mo of aldose reductase inhibitor (ARI) treatment and compared to 15 carefully age-matched control subjects. Diabetic microvessels showed basement membrane thickening and loss of endothelial cell tight junctions. Microvascular density and the frequency of microvessels closed by endothelial cells increased with age in diabetic and control nerves and were unaffected by diabetes. The density of microvessels showing patent lumina did not differ between control and diabetic subjects and was not related to age or diabetes. Closed microvessels were composed of postcapillary venules that were otherwise devoid of ultrastructural abnormalities. We suggest that microvascular closure by endothelial cells may be a physiological condition and is unlikely to have any pathogenetic significance in diabetic neuropathy. Based on the current limited biopsy material, we conclude that 12 mo of ARI treatment that induced significant fiber repair and regeneration had no detectable effect on endoneurial microvascular abnormalities. These data suggest that endoneurial vascular pathology is not a rate-limiting factor in fiber damage or repair at this stage of diabetic neuropathy.