Role of endothelial Raptor in abnormal arteriogenesis after lower limb ischaemia in type 2 diabetes.

Autor:	Liu T; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China., Zhang J; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China., Chang F; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China., Sun M; Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China., He J; Department of Physiology and Pathophysiology, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China., Ai D; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China.; Department of Physiology and Pathophysiology, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2024 Sep 02; Vol. 120 (10), pp. 1218-1234.
DOI:	10.1093/cvr/cvae105
Abstrakt:	Aims: Proper arteriogenesis after tissue ischaemia is necessary to rebuild stable blood circulation; nevertheless, this process is impaired in type 2 diabetes mellitus (T2DM). Raptor is a scaffold protein and a component of mammalian target of rapamycin complex 1 (mTORC1). However, the role of the endothelial Raptor in arteriogenesis under the conditions of T2DM remains unknown. This study investigated the role of endothelial Raptor in ischaemia-induced arteriogenesis during T2DM. Methods and Results: Although endothelial mTORC1 is hyperactive in T2DM, we observed a marked reduction in the expression of endothelial Raptor in two mouse models and in human vessels. Inducible endothelial-specific Raptor knockout severely exacerbated impaired hindlimb perfusion and arteriogenesis after hindlimb ischaemic injury in 12-week high-fat diet fed mice. Additionally, we found that Raptor deficiency dampened vascular endothelial growth factor receptor 2 (VEGFR2) signalling in endothelial cells (ECs) and inhibited VEGF-induced cell migration and tube formation in a PTP1B-dependent manner. Furthermore, mass spectrometry analysis indicated that Raptor interacts with neuropilin 1 (NRP1), the co-receptor of VEGFR2, and mediates VEGFR2 trafficking by facilitating the interaction between NRP1 and Synectin. Finally, we found that EC-specific overexpression of the Raptor mutant (loss of mTOR binding) reversed impaired hindlimb perfusion and arteriogenesis induced by endothelial Raptor knockout in high-fat diet fed mice. Conclusion: Collectively, our study demonstrated the crucial role of endothelial Raptor in promoting ischaemia-induced arteriogenesis in T2DM by mediating VEGFR2 signalling. Thus, endothelial Raptor is a novel therapeutic target for promoting arteriogenesis and ameliorating perfusion in T2DM. Competing Interests: Conflict of interest: none declared. (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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