title: Endothelial dysfunction and altered mechanical and structural properties of resistance arteries in a murine model of graft-versus-host disease.
abstract: A putative involvement of the vasculature seems to play a critical role in the pathophysiology of graft-versus-host disease (GVHD). We aimed to characterize alterations of mesenteric resistance arteries in GVHD in a fully MHC-mismatched model of BALB/c mice conditioned with total body irradiation that underwent transplantation with bone marrow cells and splenocytes from syngeneic (BALB/c) or allogeneic (C57BL/6) donors. After 4 weeks, animals were sacrificed and mesenteric resistance arteries were studied in a pressurized myograph. The expression of endothelial (eNOS) and inducible nitric oxide (NO)-synthase (iNOS) was quantified and vessel wall ultrastructure was investigated with electron microscopy. The myograph study revealed an endothelial dysfunction in allogeneic-transplant recipients, whereas endothelium-independent vasodilation was similar to syngeneic-transplant recipients or untreated controls. The expression of eNOS was decreased and iNOS increased, possibly contributing to endothelial dysfunction. Additionally, arteries of allogeneic transplant recipients exhibited a geometry-independent increase in vessels strain. For both findings, electron microscopy provided a structural correlate by showing severe damage of the whole vessel wall in allogeneic-transplant recipient animals. Our study provides further data to prove, and is the first to characterize, functional and structural vascular alterations in the early course after allogeneic transplantation directly in an ex vivo setting and, therefore, strongly supports the hypothesis of a vascular form of GVHD.
authors.affiliation: Medical Clinic 2, Cardiology, University Hospital Regensburg, Germany. Electronic address: peterm.schmid@ukr.dr.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schmid
authors.affiliation: Medical Clinic 3, Hematology/Oncology, University Hospital Regensburg, Germany.
authors.forename: Abdellatif
authors.initials: A
authors.lastname: Bouazzaoui
authors.affiliation: Medical Clinic 3, Hematology/Oncology, University Hospital Regensburg, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Doser
authors.affiliation: Medical Clinic 3, Hematology/Oncology, University Hospital Regensburg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Schmid
authors.affiliation: Medical Clinic 3, Hematology/Oncology, University Hospital Regensburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Institute for Pathology, University Hospital Regensburg, Germany.
authors.forename: Josef A
authors.initials: JA
authors.lastname: Schroeder
authors.affiliation: Medical Clinic 2, Cardiology, University Hospital Regensburg, Germany.
authors.forename: Guenter A
authors.initials: GA
authors.lastname: Riegger
authors.affiliation: Medical Clinic 3, Hematology/Oncology, University Hospital Regensburg, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Holler
authors.affiliation: Medical Clinic 2, Cardiology, University Hospital Regensburg, Germany.
authors.forename: Dierk H
authors.initials: DH
authors.lastname: Endemann
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D008285:Major Histocompatibility Complex; D008638:Mesenteric Arteries / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009213:Myography; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D014655:Vascular Resistance; D014916:Whole-Body Irradiation
chemical_list: D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse
keywords: Compliance of resistance arteries; Endothelial dysfunction; Endothelial nitric oxide synthase (eNOS); Graft-versus-host disease; Inducible nitric oxide synthase (iNOS)