title: Endothelial Cell Apoptosis Induces TGF-β Signaling-Dependent Host Endothelial-Mesenchymal Transition to Promote Transplant Arteriosclerosis.
abstract: Endothelial cells (ECs) apoptosis is an initial event in transplant arteriosclerosis (TA), resulting in allograft function loss. To elucidate the precise mechanisms of ECs apoptosis leading to neointimal smooth muscle cells (SMCs) accumulation during TA. We induced apoptosis in cultured ECs by overexpressing p53 through lentivirus-mediated transfection. ECs apoptosis induced the production of transforming growth factor (TGF)-β1 in both apoptotic and neighboring viable cells, leading to increased TGF-β1 in the culture media. Conditioned media from Ltv-p53-transfected ECs further promoted transition of cultured ECs to SM-like cells by activating TGF-β/Smad3, PI3K/Akt/mTOR, and MAPK/ERK signaling in a TGF-β-dependent manner. In transgenic rat aorta transplantation models, inhibition of ECs apoptosis in Bcl-xL(+/+) knock-in rat aortic allografts significantly reduced TGF-β1 production both in allograft endothelia and in blood plasma, which in turn decreased accumulation of SM22α+ cells from transgenic recipient ECs originally marked with EGFP knock-in in neointima and alleviated TA. Systemic treatment with SIS3, AP23573, or PD98059 also prevented recipient ECs-originated SM-like cells accumulation and intima hyperplasia in aortic allografts. These data suggest that allograft EC apoptosis induced recipient endothelial-mesenchymal (smooth muscle) transition via TGF-β signaling, resulting in recipient EC-derived SMC accumulation as a major mechanism of vascular remodeling during TA.
authors.affiliation: Department of Urology Oncological Surgery, Chongqing Cancer Hospital & Institute & Cancer Center, Chongqing, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery and Liver Transplantation Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, China.
authors.forename: J
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Department of Hepatobiliary Surgery and Liver Transplantation Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, China.
authors.forename: B
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Gynecologic Oncology, Chongqing Cancer Hospital & Institute & Cancer Center, Chongqing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Radiotherapy, Chongqing Cancer Hospital & Institute & Cancer Center, Chongqing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Urology Oncological Surgery, Chongqing Cancer Hospital & Institute & Cancer Center, Chongqing, China.
authors.forename: H
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Urology Oncological Surgery, Chongqing Cancer Hospital & Institute & Cancer Center, Chongqing, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Urology Oncological Surgery, Chongqing Cancer Hospital & Institute & Cancer Center, Chongqing, China.
authors.forename: N
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Urology Oncological Surgery, Chongqing Cancer Hospital & Institute & Cancer Center, Chongqing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery and Liver Transplantation Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Song
authors.affiliation: Department of Hepatobiliary Surgery and Liver Transplantation Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zheng
mesh_terms: D064591:Allografts; D000818:Animals; D001011:Aorta / Q000637:transplantation*; D017209:Apoptosis; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005455:Fluorescent Antibody Technique; D007124:Immunoenzyme Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases
keywords: basic (laboratory) research/science; cell death: apoptosis; cellular biology; cytokines/cytokine receptors; pathology/histopathology; rejection: chronic; signaling/signaling pathways; vascularized composite and reconstructive transplantation; vasculopathy