Reduced Vascular Endothelial Growth Factor Expression and Intra-Epidermal Nerve Fiber Loss in Human Diabetic Neuropathy

Abstract

OBJECTIVE -To assess the relevance of vascular endothelial growth factor (VEGF) in the maintenance of peripheral nerve integrity in diabetic neuropathy we have assessed the expression of VEGF and intra-epidermal nerve fiber density (IENFD) in skin biopsy samples from diabetic patients.RESEARCH DESIGN AND METHODS -Fifty-three diabetic patients and 12 nondiabetic control subjects underwent neurological evaluation, electrophysiology, quantitative sensory, and autonomic function testing. Dermal blood flow responses were evaluated with laser Doppler flowmetry. Skin biopsies were performed on the dorsum of the foot, and IENFD was quantified and compared with the expression of vascular endothelial growth factor A (VEGF-A), its receptor vascular endothelial growth factor receptor 2 (VEGFR-2), hypoxia-inducible factor 1␣ (HIF-1␣), and microvessel density.RESULTS -IENFD decreased progressively with increasing severity of diabetic neuropathy (P Ͻ 0.001). The dermal blood flow response to acetylcholine was reduced in diabetic patients with mild and moderate neuropathy (P Ͻ 0.01), and the intensity of staining for epidermal VEGF-A was significantly reduced in diabetic patients compared with control subjects (P Ͻ 0.01). Epidermal HIF-1␣ and VEGFR-2 expression did not differ between groups.CONCLUSIONS -Progressive endothelial dysfunction, a reduction in VEGF expression, and loss of intra-epidermal nerve fibers occurs in the foot skin of diabetic patients with increasing neuropathic severity.

Overexpression of cutaneous mitochondrial superoxide dismutase in recent-onset type 2 diabetes

“…This differs from the study by Quattrini et al [10] showing that the density of dermal microvessels (number/mm 2 ) was increased in patients with diabetes who had moderate polyneuropathy, but reduced in those without polyneuropathy or with only mild polyneuropathy. There may be two reasons for this disparity.…”

“…First, we did not quantify microvessel density but endothelial cell area, as the latter provides an estimate of the total microvascular supply. Second, we studied a population with recent-onset diabetes, while the duration of diabetes in the groups studied by Quattrini et al [10] ranged between 15 and 28 years. It is thus possible that alterations in the dermal microvasculature develop only at a later stage of type 2 diabetes.…”

The Neuropad test: a visual indicator test for human diabetic neuropathy

“…The correlation between the Neuropad response and IENFD was poorer than with the other measures of neuropathy. We can only speculate that assessing IENFD, which provides a structural measure of the number of fibres, may not reflect nerve fibre and specifically sudomotor nerve function [25], as recent studies certainly suggest that IENFD relates well to other measures of somatic neuropathy [26,27]. Nevertheless, as IENFD is widely accepted as a gold standard measure of skin denervation and neuropathy [26][27][28], we believe these findings add strength to the assertion that Neuropad reflects the severity of distal somatic neuropathy.…”

Early Detection of Nerve Fiber Loss by Corneal Confocal Microscopy and Skin Biopsy in Recently Diagnosed Type 2 Diabetes

“…This is in line with the aforementioned studies (12,32,34) supporting the notion that the pathophysiology underlying the manifestation of neuropathy in the cornea may be different from DSPN affecting the lower limbs. Indeed, vascular factors including reduced endoneurial blood flow and microvascular alterations appear to contribute to the pathogenesis of DSPN (35,36), whereas the normal cornea, albeit being the most densely innervated tissue in the human body (several 100-fold higher than skin) (37), is devoid of blood vessels. However, many corneal abnormalities may disrupt the avascular microenvironment and lead to corneal angiogenesis.…”