Microvasculopathic neuromuscular diseases: lessons from hypoxia-inducible factors.
Dermatomyositis and vasculitic neuropathies are disorders with immune mediated ischemic injuries. Cellular responses to hypoxia include the hypoxia-inducible factor-1 (HIF-1)-induced transcription of genes involved in angiogenesis. To study their possible roles in those disorders, the immunohistochemical expression of HIF-1alpha, HIF-1beta, HIF-2alpha, vascular endothelial growth factor (VEGF), VEGF-receptor (VEGF-R) and erythropoietin-receptor was investigated. Cases of normal nerves, diabetic neuropathy, normal muscles, polymyositis and inclusion-body-myositis served as controls. The latter were chosen because they represent comparable inflammatory disorders, however, in these ischemia/hypoxia is not supposed to play such a prominent pathogenetic role. Hypoxia-related proteins were not detected in normal controls. In polymyositis and inclusion-body-myositis, there was VEGF-R-expression in muscle fibers and HIF-2alpha reactivity in endothelial cells. In dermatomyositis, HIF-1alpha and HIF-1beta were found in endothelial cells, whereas HIF-2alpha, erythropoietin-receptor, VEGF and VEGF-R additionally were observed in muscle fibers. In vasculitic and diabetic neuropathies, a variable focal expression of hypoxia-inducible factors, VEGF, VEGF-R and erythropoietin-receptor was seen in vessels. These observations suggest that the upregulation of hypoxia-related proteins may represent an adaptation mechanism of neuromuscular tissues to immune mediated deprivation of the blood supply.
Probst-Cousin
Stefan
S
Department of Neurology, Klinikum Bremen-Ost, Bremen, Germany. stefan.probst@klinikum-bremen-ost.de
Neundörfer
Bernhard
B
Heuss
Dieter
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D036388:Ephrin-B2 / Q000378:metabolism; D005260:Female; D018840:HSP70 Heat-Shock Proteins; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D055806:Microvessels / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000378:metabolism; D009468:Neuromuscular Diseases / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D011506:Proteins / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D043925:Angiogenesis Inducing Agents; D051792:Basic Helix-Loop-Helix Proteins; D036388:Ephrin-B2; D018840:HSP70 Heat-Shock Proteins; D051793:Hypoxia-Inducible Factor 1; D011506:Proteins; D017467:Receptors, Erythropoietin; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C050087:oxygen-regulated proteins