PDF(Pubmed)
Abstract：
Matrix Gla protein (MGP) is a small secreted protein and requires vitamin K dependent γ-carboxylation for its function. MGP has been identified as a local inhibitor of vascular calcification because MGP-deficient mice die due to severe arterial calcification and resulting arterial rupture. Clinical trials revealed that reduction in active MGP predicts poor prognosis in patients due to cardiovascular complications. However, recent studies showed that MGP controls angiogenesis during development. MGP-deficient mice demonstrated abnormal hypervascularization and arteriovenous malformations in kidneys and other organs. This abnormal angiogenesis is largely caused by excessive expression of vascular endothelial growth factor-A (VEGF-A) and VEGF receptor-2 (VEGFR2). However, only a few studies have investigated the roles of MGP in tissue injury. We observed mesangial cell proliferation and mild interstitial fibrosis in addition to increased capillaries in kidneys of MGP-null mice even without injury. We also created a mouse model with kidney injury and found that kidney damage greatly increases MGP expression in peritubular capillary endothelial cells and tubular epithelial cells. Finally, our study showed that impairment of MGP expression aggravates peritubular capillary rarefaction and accumulation of collagen-producing myofibroblasts following kidney injury. Peritubular capillary damage induces capillary loss as well as trans-differentiation of vascular pericytes into myofibroblasts. These results indicate that MGP has the vascular protective effect in the injured kidney. Clinical trials have already started to test the efficacy of MGP activation to repair vascular calcification in patients with chronic kidney diseases. In this \"Hypothesis and Theory\" article, we discuss possible mechanisms by which MGP protects against vascular damage during tissue injury based on our experimental results and previous results from other research groups.
摘要：
基质Gla蛋白（MGP）是一种小的分泌蛋白，其功能需要维生素K依赖性γ-羧化作用。MGP已被鉴定为血管钙化的局部抑制剂,因为缺乏MGP的小鼠由于严重的动脉钙化和导致的动脉破裂而死亡。临床试验表明，活动性MGP的减少预示着由于心血管并发症而导致的患者预后不良。然而,最近的研究表明，MGP在发育过程中控制血管生成。MGP缺陷小鼠在肾脏和其他器官中表现出异常的血管过度形成和动静脉畸形。这种异常血管生成主要由血管内皮生长因子-A(VEGF-A)和VEGF受体-2(VEGFR2)的过度表达引起。然而,只有少数研究研究了MGP在组织损伤中的作用。我们观察到肾小球系膜细胞增殖和轻度间质纤维化，以及MGP无效小鼠肾脏中毛细血管增加，即使没有损伤。我们还创建了肾损伤小鼠模型，发现肾损伤会大大增加肾小管周围毛细血管内皮细胞和肾小管上皮细胞中MGP的表达。最后,我们的研究表明,MGP表达受损会加重肾损伤后肾小管周围毛细血管的稀疏和产生胶原的肌成纤维细胞的积累.肾小管周围毛细血管损伤引起毛细血管损失以及血管周细胞转分化为肌成纤维细胞。这些结果表明MGP在受损的肾脏中具有血管保护作用。临床试验已经开始测试MGP激活修复慢性肾脏疾病患者血管钙化的功效。在这篇“假设与理论”文章中，我们根据我们的实验结果和其他研究组以前的结果,讨论了MGP在组织损伤过程中防止血管损伤的可能机制.
