title: Thrombomodulin deficiency in human diabetic nerve microvasculature.
abstract: Human diabetic neuropathy is multifactorial in etiology, with ischemia as a final common pathology. Although impaired vascular endothelial cell function in diabetic microvascular injury is established, the role of thrombomodulin (TM)-dependent protein C antithrombotic mechanism in the pathogenesis of neuropathy is unclear. This neuropathologic case-control study investigated whether vascular endothelial TM expression is deficient in peripheral nerve microvessels in diabetic neuropathy. Sural nerve biopsies from 7 patients with diabetic neuropathy and 10 with axonal neuropathy without vasculopathy were immunostained with anti-TM and anti-von Willebrand factor (vWF; an endothelial cell marker) antibodies. The proportion of TM-positive microvessels was expressed relative to total vWF-staining vessels, according to vessel caliber and regional distribution within the nerve. In diabetic nerves compared with reference controls, the proportion of TM-positive endoneurial microvessels was 15-fold lower (0.02 vs. 0.30 in diabetic nerves vs. controls, P < 0.004), and the proportion of small-caliber epineurial microvessels was 10-fold lower (0.04 vs. 0.43, P < 0.001). No TM expression was detected at the perineurium in diabetic or control nerves. We demonstrate a substantial reduction of vascular endothelial TM expression throughout human diabetic neuropathy. These findings suggest that an impaired native TM-dependent protein C antithrombotic mechanism may contribute to microvascular ischemia in the pathogenesis of diabetic neuropathy.
authors.affiliation: Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland 21201-1595, USA. cmacko@grecc.umaryland.edu
authors.forename: Charlene E
authors.initials: CE
authors.lastname: Hafer-Macko
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Ivey
authors.forename: Kymberly A
authors.initials: KA
authors.lastname: Gyure
authors.forename: John D
authors.initials: JD
authors.lastname: Sorkin
authors.forename: Richard F
authors.initials: RF
authors.lastname: Macko
mesh_terms: D000328:Adult; D000368:Aged; D001369:Axons / Q000473:pathology; D001706:Biopsy; D016022:Case-Control Studies; D003929:Diabetic Neuropathies / Q000209:etiology* / Q000473:pathology; D004730:Endothelium, Vascular / Q000737:chemistry; D005260:Female; D006801:Humans; D007511:Ischemia / Q000150:complications; D008297:Male; D008833:Microcirculation / Q000737:chemistry* / Q000473:pathology; D008875:Middle Aged; D010525:Peripheral Nerves / Q000098:blood supply*; D011486:Protein C / Q000502:physiology; D013497:Sural Nerve / Q000473:pathology; D018180:Thrombomodulin / Q000172:deficiency* / Q000502:physiology; D013927:Thrombosis / Q000517:prevention & control; D014841:von Willebrand Factor / Q000032:analysis
chemical_list: D011486:Protein C; D018180:Thrombomodulin; D014841:von Willebrand Factor