Department of Neurobiology and Research Institute for Aging and Medicine, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 138 Yi-Xue-Yuan Road, Shanghai, 200032, People's Republic of China.
National Clinical Research Center for Aging and Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
Cell Mol Neurobiol. 2023 Oct;43(7):3575-3592. doi: 10.1007/s10571-023-01366-0. Epub 2023 Jul 7.
It has been demonstrated that diabetes cause neurite degeneration in the brain and cognitive impairment and neurovascular interactions are crucial for maintaining brain function. However, the role of vascular endothelial cells in neurite outgrowth and synaptic formation in diabetic brain is still unclear. Therefore, present study investigated effects of brain microvascular endothelial cells (BMECs) on high glucose (HG)-induced neuritic dystrophy using a coculture model of BMECs with neurons. Multiple immunofluorescence labelling and western blot analysis were used to detect neurite outgrowth and synapsis formation, and living cell imaging was used to detect uptake function of neuronal glucose transporters. We found cocultured with BMECs significantly reduced HG-induced inhibition of neurites outgrowth (including length and branch formation) and delayed presynaptic and postsynaptic development, as well as reduction of neuronal glucose uptake capacity, which was prevented by pre-treatment with SU1498, a vascular endothelial growth factor (VEGF) receptor antagonist. To analyse the possible mechanism, we collected BMECs cultured condition medium (B-CM) to treat the neurons under HG culture condition. The results showed that B-CM showed the same effects as BMEC on HG-treated neurons. Furthermore, we observed VEGF administration could ameliorate HG-induced neuronal morphology aberrations. Putting together, present results suggest that cerebral microvascular endothelial cells protect against hyperglycaemia-induced neuritic dystrophy and restorate neuronal glucose uptake capacity by activation of VEGF receptors and endothelial VEGF release. This result help us to understand important roles of neurovascular coupling in pathogenesis of diabetic brain, providing a new strategy to study therapy or prevention for diabetic dementia. Hyperglycaemia induced inhibition of neuronal glucose uptake and impaired to neuritic outgrowth and synaptogenesis. Cocultured with BMECs/B-CM and VEGF treatment protected HG-induced inhibition of glucose uptake and neuritic outgrowth and synaptogenesis, which was antagonized by blockade of VEGF receptors. Reduction of glucose uptake may further deteriorate impairment of neurites outgrowth and synaptogenesis.
已有研究表明，糖尿病可导致大脑中的轴突变性和认知障碍，而神经血管相互作用对于维持大脑功能至关重要。然而，血管内皮细胞在糖尿病大脑中的轴突生长和突触形成中的作用尚不清楚。因此，本研究采用脑微血管内皮细胞（BMEC）与神经元共培养模型，研究了 BMEC 对高糖（HG）诱导的轴突营养不良的影响。采用多重免疫荧光标记和 Western blot 分析检测轴突生长和突触形成，采用活细胞成像检测神经元葡萄糖转运体的摄取功能。结果发现，与 BMEC 共培养可显著减轻 HG 诱导的轴突生长抑制（包括长度和分支形成）和突触前、后发育延迟，以及神经元葡萄糖摄取能力降低，而 VEGF 受体拮抗剂 SU1498 预处理可预防这些变化。为分析可能的机制，我们收集 BMEC 培养的条件培养基（B-CM），在 HG 培养条件下处理神经元。结果表明，B-CM 对 HG 处理的神经元具有与 BMEC 相同的作用。此外，我们观察到 VEGF 给药可改善 HG 诱导的神经元形态异常。综上所述，本研究结果表明，脑微血管内皮细胞通过激活 VEGF 受体和内皮细胞 VEGF 释放，可防止高血糖诱导的轴突营养不良，并恢复神经元的葡萄糖摄取能力。这一结果有助于我们理解神经血管耦联在糖尿病性脑发病机制中的重要作用，为研究糖尿病性痴呆的治疗或预防提供了新策略。高血糖诱导的神经元葡萄糖摄取抑制和轴突生长及突触形成受损。与 BMEC/B-CM 共培养和 VEGF 处理可保护 HG 诱导的葡萄糖摄取和轴突生长及突触形成抑制，而 VEGF 受体阻断可拮抗这种作用。葡萄糖摄取减少可能进一步加重轴突生长和突触形成受损。
