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NEUROLOGY 2007;69:268-274
© 2007 American Academy of Neurology

Microvascular tissue plasminogen activator is reduced in diabetic neuropathy

Charlene E. Hafer-Macko, MD, Frederick M. Ivey, PhD, John D. Sorkin, MD, PhD and Richard F. Macko, MD

From the Departments of Neurology (C.E.H.-M., R.F.M.) and Gerontology (F.M.I., J.D.S.), University of Maryland School of Medicine; and the Baltimore Veterans Administration Medical Center–Geriatrics Research, Education, and Clinical Center (C.E.H.-M., F.M.I., J.D.S., R.F.M.), Baltimore, MD.

Address correspondence and reprint requests to Dr. Charlene Hafer-Macko, Department of Neurology, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201-1595; cmacko{at}grecc.umaryland.edu

Background: Abnormalities of endogenous fibrinolysis are linked to diabetic macrovascular disease; whether key vascular endothelial regulatory proteins, such as tissue plasminogen activator (tPA), are altered in diabetic neuropathy microvasculature is unknown. This neuropathologic case: control study investigates the hypothesis that tPA expression is regionally deficient in microvessels in human diabetic neuropathy.

Methods: tPA and von Willebrand factor (vWF), a vascular endothelial cell marker, are detected on vascular endothelium by immunoperoxidase methods with specific antibodies on formalin fixed paraffin embedded sural nerve biopsies from six diabetic and six axonal neuropathy control nerves without vasculopathy. The proportion of microvessels in each nerve region expressing tPA is determined by the ratio of tPA positive vessels/total vWF positive vessels on serial sections.

Results: tPA expression is lower in diabetic neuropathy cases compared to controls in all regions, including epineurial (62.4 ± 8.6% vs 91.0 ± 1.6%, p < 0.02) and endoneurial microvessels (51.7 ± 7.1% vs 91.5 ± 2.9%, p < 0.001).

Conclusions: These results demonstrate a four- to sixfold increase in the number of peripheral nerve microvessels lacking immunodetectable tissue plasminogen activator in the epineurial and endoneurial vessels in diabetes, suggesting that impaired endogenous fibrinolysis might contribute to microvascular ischemia in human diabetic neuropathy.

Supported by National Institutes of Health, National Institute of Diabetes and Digestion and Kidney Diseases 1R01 DK59758-01; National Institutes of Health, National Institute of Neurological Disorders and Stroke 1K08NS01595; Baltimore Veterans Administration Medical Center–Geriatrics Research, Education, and Clinical Center.

Disclosure: The authors report no conflicts of interest.

Received December 7, 2006. Accepted in final form February 27, 2007.






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