Ming Liang1, Yun Wang1, Anlin Liang1, Jin-Fei Dong1, Jie Du1, Jizhong Cheng2. 1. 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.). 2. 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.
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. APPROACH AND 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.
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. APPROACH AND 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.
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