Tyrosine Kinase Receptor B Protects Against Coronary Artery Disease and Promotes Adult Vasculature Integrity by Regulating Ets1-Mediated VE-Cadherin Expression

Objective— Tyrosine kinase receptor B (TrkB) is a high-affinity receptor for brain-derived neurotrophic factor. In addition to its nervous system functions, TrkB is also expressed in the cardiovascular system. However, the association of TrkB and coronary artery disease (CAD) remains unknown. We investigated the role of TrkB in the development of CAD and its mechanism. Approach and Results— We performed a case–control study in 2 independent cohort of Chinese subjects and found –69C>G polymorphisms of TrkB gene significantly associated with CAD. TrkB –69C homozygotes, which corresponded to decreased TrkB expression by luciferase reporter assay, showed increased risk for CAD. Immunofluorescence analysis revealed that TrkB was expressed in the aortic endothelium in atherosclerotic lesions in humans and ApoE –/– mice. TrkB knockdown in the aortic endothelium resulted in vascular leakage in ApoE –/– mice. Mechanistic studies showed that TrkB regulated vascular endothelial cadherin (VE-cadherin) expression through induction and activation of Ets1 transcriptional factor. Importantly, TrkB activation attenuated proatherosclerotic factors induced-endothelial hyperpermeability in human vascular endothelial cells. Conclusions— Our data demonstrate that TrkB protects endothelial integrity during atherogenesis by promoting Ets1-mediated VE-cadherin expression and plays a previously unknown protective role in the development of CAD.