Tun Wang1, Jia Liu1, Haiyang Liu2, Shin-Rong Lee2, Luis Gonzalez2, Jolanta Gorecka2, Chang Shu3, Alan Dardik4. 1. Department of Vascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; The Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut; Department of Surgery, Yale School of Medicine, New Haven, Connecticut; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut. 2. The Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut; Department of Surgery, Yale School of Medicine, New Haven, Connecticut; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut. 3. Department of Vascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; State Key Laboratory of Cardiovascular Disease, Center of Vascular Surgery, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 4. The Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut; Department of Surgery, Yale School of Medicine, New Haven, Connecticut; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut; Department of Surgery, VA Connecticut Healthcare System, West Haven, Connecticut. Electronic address: alan.dardik@yale.edu.
Abstract
BACKGROUND: Arteriovenous fistulae (AVF) are the preferred mode of vascular access for hemodialysis. Before use, AVF remodel by thickening and dilating to achieve a functional conduit via an adaptive process characterized by expression of molecular markers characteristic of both venous and arterial identity. Although signaling via EphB4, a determinant of venous identity, mediates AVF maturation, the role of its counterpart EphrinB2, a determinant of arterial identity, remains unclear. We hypothesize that EphrinB2 signaling is active during AVF maturation and may be a mechanism of venous remodeling. METHODS: Aortocaval fistulae were created or sham laparotomy was performed in C57Bl/6 mice, and specimens were examined on Days 7 or 21. EphrinB2 reverse signaling was activated with EphB4-Fc applied periadventitially in vivo and in endothelial cell culture medium in vitro. Downstream signaling was assessed using immunoblotting and immunofluorescence. RESULTS: Venous remodeling during AVF maturation was characterized by increased expression of EphrinB2 as well as Akt1, extracellular signal-regulated kinases 1/2 (ERK1/2), and p38. Activation of EphrinB2 with EphB4-Fc increased phosphorylation of EphrinB2, endothelial nitric oxide synthase, Akt1, ERK1/2, and p38 and was associated with increased diameter and wall thickness in the AVF. Both mouse and human endothelial cells treated with EphB4-Fc increased phosphorylation of EphrinB2, endothelial nitric oxide synthase, Akt1, ERK1/2, and p38 and increased endothelial cell tube formation and migration. CONCLUSIONS: Activation of EphrinB2 signaling by EphB4-Fc was associated with adaptive venous remodeling in vivo while activating endothelial cell function in vitro. Regulation of EphrinB2 signaling may be a new strategy to improve AVF maturation and patency. Published by Elsevier Inc.
BACKGROUND: Arteriovenous fistulae (AVF) are the preferred mode of vascular access for hemodialysis. Before use, AVF remodel by thickening and dilating to achieve a functional conduit via an adaptive process characterized by expression of molecular markers characteristic of both venous and arterial identity. Although signaling via EphB4, a determinant of venous identity, mediates AVF maturation, the role of its counterpart EphrinB2, a determinant of arterial identity, remains unclear. We hypothesize that EphrinB2 signaling is active during AVF maturation and may be a mechanism of venous remodeling. METHODS: Aortocaval fistulae were created or sham laparotomy was performed in C57Bl/6 mice, and specimens were examined on Days 7 or 21. EphrinB2 reverse signaling was activated with EphB4-Fc applied periadventitially in vivo and in endothelial cell culture medium in vitro. Downstream signaling was assessed using immunoblotting and immunofluorescence. RESULTS: Venous remodeling during AVF maturation was characterized by increased expression of EphrinB2 as well as Akt1, extracellular signal-regulated kinases 1/2 (ERK1/2), and p38. Activation of EphrinB2 with EphB4-Fc increased phosphorylation of EphrinB2, endothelial nitric oxide synthase, Akt1, ERK1/2, and p38 and was associated with increased diameter and wall thickness in the AVF. Both mouse and human endothelial cells treated with EphB4-Fc increased phosphorylation of EphrinB2, endothelial nitric oxide synthase, Akt1, ERK1/2, and p38 and increased endothelial cell tube formation and migration. CONCLUSIONS: Activation of EphrinB2 signaling by EphB4-Fc was associated with adaptive venous remodeling in vivo while activating endothelial cell function in vitro. Regulation of EphrinB2 signaling may be a new strategy to improve AVF maturation and patency. Published by Elsevier Inc.
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