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

• Published in: Cardiovascular research Vol. 120; no. 10; pp. 1218 - 1234
• Main Authors: Liu, Ting, Zhang, Jiachen, Chang, Fangyuan, Sun, Mengyu, He, Jinlong, Ai, Ding
• Format: Journal Article
• Language: English
• Published: UK Oxford University Press 02.09.2024
• Subjects: Animals; Cell Movement; Cells, Cultured; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetic Angiopathies - etiology; Diabetic Angiopathies - genetics; Diabetic Angiopathies - metabolism; Diabetic Angiopathies - pathology; Diabetic Angiopathies - physiopathology; Disease Models, Animal; Endothelial Cells - metabolism; Endothelial Cells - pathology; Hindlimb - blood supply; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Ischemia - genetics; Ischemia - metabolism; Ischemia - pathology; Ischemia - physiopathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal - blood supply; Muscle, Skeletal - metabolism; Neovascularization, Physiologic; Regional Blood Flow; Regulatory-Associated Protein of mTOR - deficiency; Regulatory-Associated Protein of mTOR - genetics; Regulatory-Associated Protein of mTOR - metabolism; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Arteriogenesis; T2DM; Endothelial cell; VEGF; Raptor
• ISSN: 0008-6363; 1755-3245; 1755-3245
• DOI: 10.1093/cvr/cvae105

Abstract 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. Graphical Abstract Graphical Abstract