title: Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100.
abstract: Acute graft-versus-host disease (GvHD) is a complex process involving endothelial damage and neovascularization. Better understanding of the pathophysiology of neovascularization during GvHD could help to target this process while leaving T-cell function intact. Under ischemic conditions, neovascularization is regulated by different micro RNAs (miRs), which potentially play a role in inflamed hypoxic GvHD target organs. We observed strong neovascularization in the murine inflamed intestinal tract (IT) during GvHD. Positron emission tomography imaging demonstrated abundant αvβ3 integrin expression within intestinal neovascularization areas. To interfere with neovascularization, we targeted αv integrin-expressing endothelial cells, which blocked their accumulation in the IT and reduced GvHD severity independent of immune reconstitution and graft-versus-tumor effects. Additionally, enhanced neovascularization and αv integrin expression correlated with GvHD severity in humans. Expression analysis of miRs in the inflamed IT of mice developing GvHD identified miR-100 as significantly downregulated. Inactivation of miR-100 enhanced GvHD indicating a protective role for miR-100 via blocking inflammatory neovascularization. Our data from the mouse model and patients indicate that inflammatory neovascularization is a central event during intestinal GvHD that can be inhibited by targeting αv integrin. We identify negative regulation of GvHD-related neovascularization by miR-100, which indicates common pathomechanistic features of GvHD and ischemia.
authors: Department of Hematology and Oncology, FreiburgUniversity Medical Center, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors: Franziska
authors: F
authors: Leonhardt
authors: Sebastian
authors: S
authors: Grundmann
authors: Martin
authors: M
authors: Behe
authors: Franziska
authors: F
authors: Bluhm
authors: Rebecca A
authors: RA
authors: Dumont
authors: Friederike
authors: F
authors: Braun
authors: Melpomeni
authors: M
authors: Fani
authors: Katarina
authors: K
authors: Riesner
authors: Gabriele
authors: G
authors: Prinz
authors: Anne-Kathrin
authors: AK
authors: Hechinger
authors: Ulrike V
authors: UV
authors: Gerlach
authors: Heide
authors: H
authors: Dierbach
authors: Olaf
authors: O
authors: Penack
authors: Annette
authors: A
authors: Schmitt-Gräff
authors: Jürgen
authors: J
authors: Finke
authors: Wolfgang A
authors: WA
authors: Weber
authors: Robert
authors: R
authors: Zeiser
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D039564:Integrin alphaV / Q000235:genetics / Q000378:metabolism*; D007410:Intestinal Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009389:Neovascularization, Pathologic; D049268:Positron-Emission Tomography; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D039564:Integrin alphaV; C544266:MIRN100 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger