Department of Pharmacology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
Department of Pharmacology and Convergence Medical Science, College of Medicine, Gyeongsang National University, Jinju 52727, Korea.
Int J Mol Sci. 2020 Nov 12;21(22):8538. doi: 10.3390/ijms21228538.
The progressive neurodegeneration in Parkinson's disease (PD) is accompanied by neuroinflammation and endothelial vascular impairment. Although the vitamin D receptor (VDR) is expressed in both dopamine neurons and brain endothelial cells, its role in the regulation of endothelial biology has not been explored in the context of PD. In a 6-hydroxydopamine (6-OHDA)-induced PD mouse model, we observed reduced transcription of the VDR and its downstream target genes, and . The 6-OHDA-induced transcriptional repression of these genes were recovered after the VDR ligand-1α,25-dihydroxyvitamin D (1,25(OH)D) treatment. Similarly, reduced vascular protein expression of P-glycoprotein (P-gp), encoded by , after 6-OHDA administration was reversed by 1,25(OH)D. Moreover, marked reduction of endothelial P-gp expression with concomitant α-synuclein aggregation was found in a combinatorial /αSyn preformed fibril (PFF) injection mouse model and postmortem PD brains. Supporting the direct effect of α-synuclein aggregation on endothelial biology, PFF treatment of human umbilical vein endothelial cells (HUVECs) was sufficient to induce α-synuclein aggregation and repress transcription of the VDR. PFF-induced P-gp downregulation and impaired functional activity in HUVECs completely recovered after 1,25(OH)D treatment. Taken together, our results suggest that a dysfunctional VDR-P-gp pathway could be a potential target for the maintenance of vascular homeostasis in PD pathological conditions.
帕金森病（PD）的进行性神经退行性变伴随着神经炎症和血管内皮损伤。尽管维生素 D 受体（VDR）在多巴胺神经元和脑内皮细胞中均有表达，但在 PD 背景下，其在调节内皮生物学方面的作用尚未得到探索。在 6-羟多巴胺（6-OHDA）诱导的 PD 小鼠模型中，我们观察到 VDR 及其下游靶基因 和 的转录减少。6-OHDA 诱导的这些基因的转录抑制作用在 VDR 配体 1α，25-二羟基维生素 D（1,25（OH）D）处理后得到恢复。同样，6-OHDA 给药后，编码 的血管蛋白 P-糖蛋白（P-gp）的表达减少也被 1,25（OH）D 逆转。此外，在组合 /αSyn 原纤维（PFF）注射小鼠模型和 PD 死后大脑中发现，内皮 P-gp 表达明显减少，同时伴有 α-突触核蛋白聚集。支持 α-突触核蛋白聚集对内皮生物学的直接影响，PFF 处理人脐静脉内皮细胞（HUVEC）足以诱导 α-突触核蛋白聚集并抑制 VDR 的转录。PFF 诱导的 P-gp 下调和 HUVEC 功能活性受损在 1,25（OH）D 处理后完全恢复。总之，我们的研究结果表明，功能失调的 VDR-P-gp 途径可能是维持 PD 病理条件下血管内稳态的潜在靶点。
