title: Impaired integrin β3 delays endothelial cell regeneration and contributes to arteriovenous graft failure in mice.
abstract: OBJECTIVE
  Neointima formation is associated with stenosis and subsequent thrombosis in arteriovenous grafts (AVGs). A role of integrin β3 in the neointima formation of AVGs remains poorly understood.
  
  
  RESULTS
  In integrin β3(-/-) mice, we found significantly accelerated occlusion of AVGs compared with the wild-type mice. This is caused by the development of neointima and lack of endothelial regeneration. The latter is a direct consequence of impaired functions of circulating angiogenic cells (CACs) and platelets in integrin β3(-/-) mice. Evidence suggests the involvement of platelet regulating CAC homing to and differentiation at graft sites via transforming growth factor-β1 and Notch signaling pathway. First, CACs deficient of integrin β3 impaired adhesion activity toward exposed subendothelium. Second, platelets from integrin β3(-/-) mice failed to sufficiently stimulate CACs to differentiate into mature endothelial cells. Finally, we found that transforming growth factor-β1 level was increased in platelets from integrin β3(-/-) mice and resulted in enhanced Notch1 activation in CACs in AVGs. These results demonstrate that integrin β3 is critical for endothelial cell homing and differentiation. The increased transforming growth factor-β1 and Notch1 signaling mediates integrin β3(-/-)-induced AVG occlusion. This accelerated occlusion of AVGs was reversed in integrin β3(-/-) mice transplanted with the bone marrow from wild-type mice.
  
  
  CONCLUSIONS
  Our results suggest that boosting integrin β3 function in the endothelial cells and platelets could prevent neointima and thrombosis in AVGs.
authors.affiliation: From the Department of Nephrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China (M.L.); Department of Cell Biology, Third Military Medical University, Chongqing, China (Y.W.); Puget Sound Blood Research Institute, Hematology Division, Department of Medicine, University of Washington, Seattle (J.-F.D.); Beijing Anzhen Hospital Affiliated to the Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (J.D.); and Nephrology Division, Baylor College of Medicine, Houston, TX (M.L., Y.W., A.L., J.C.).
authors.forename: Ming
authors.initials: M
authors.lastname: Liang
authors.affiliation: From the Department of Nephrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China (M.L.); Department of Cell Biology, Third Military Medical University, Chongqing, China (Y.W.); Puget Sound Blood Research Institute, Hematology Division, Department of Medicine, University of Washington, Seattle (J.-F.D.); Beijing Anzhen Hospital Affiliated to the Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (J.D.); and Nephrology Division, Baylor College of Medicine, Houston, TX (M.L., Y.W., A.L., J.C.).
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Nephrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China (M.L.); Department of Cell Biology, Third Military Medical University, Chongqing, China (Y.W.); Puget Sound Blood Research Institute, Hematology Division, Department of Medicine, University of Washington, Seattle (J.-F.D.); Beijing Anzhen Hospital Affiliated to the Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (J.D.); and Nephrology Division, Baylor College of Medicine, Houston, TX (M.L., Y.W., A.L., J.C.).
authors.forename: Anlin
authors.initials: A
authors.lastname: Liang
authors.affiliation: From the Department of Nephrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China (M.L.); Department of Cell Biology, Third Military Medical University, Chongqing, China (Y.W.); Puget Sound Blood Research Institute, Hematology Division, Department of Medicine, University of Washington, Seattle (J.-F.D.); Beijing Anzhen Hospital Affiliated to the Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (J.D.); and Nephrology Division, Baylor College of Medicine, Houston, TX (M.L., Y.W., A.L., J.C.).
authors.forename: Jin-Fei
authors.initials: JF
authors.lastname: Dong
authors.affiliation: From the Department of Nephrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China (M.L.); Department of Cell Biology, Third Military Medical University, Chongqing, China (Y.W.); Puget Sound Blood Research Institute, Hematology Division, Department of Medicine, University of Washington, Seattle (J.-F.D.); Beijing Anzhen Hospital Affiliated to the Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (J.D.); and Nephrology Division, Baylor College of Medicine, Houston, TX (M.L., Y.W., A.L., J.C.).
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.affiliation: From the Department of Nephrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China (M.L.); Department of Cell Biology, Third Military Medical University, Chongqing, China (Y.W.); Puget Sound Blood Research Institute, Hematology Division, Department of Medicine, University of Washington, Seattle (J.-F.D.); Beijing Anzhen Hospital Affiliated to the Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (J.D.); and Nephrology Division, Baylor College of Medicine, Houston, TX (M.L., Y.W., A.L., J.C.). jizhongc@bcm.edu.
authors.forename: Jizhong
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D001792:Blood Platelets / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058426:Neointima; D051881:Receptor, Notch1 / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014684:Venae Cavae / Q000378:metabolism / Q000473:pathology / Q000601:surgery*
chemical_list: D039661:Integrin beta3; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1
keywords: arteriovenous graft; circulating angiogenic cells; integrin β3; neointima