Deletion of Hyaluronan Synthase 3 Inhibits Neointimal Hyperplasia in Mice.
Deletion of Hyaluronan Synthase 3 Inhibits Neointimal Hyperplasia in Mice.
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透明质酸合酶3的缺失抑制小鼠的新内膜增生。
DOI：
10.1161/atvbaha.115.306607
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
Fischer JW
中科院分区：
文献类型：
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作者：
Kiene LS;Homann S;Suvorava T;Rabausch B;Müller J;Kojda G;Kretschmer I;Twarock S;Dai G;Deenen R;Hartwig S;Lehr S;Köhrer K;Savani RC;Grandoch M;Fischer JW
透明质酸（HA）是一种聚葡萄糖氨基聚糖，在病变血管中形成临时的细胞外基质。HA是由三种不同的HA合酶（HAS1, -2, -3）合成的。本研究的目的是揭示HAS3同工酶在实验性新生内膜增生中的作用。结扎颈动脉可诱导has3缺陷小鼠新生内膜增生。结扎后28天，has3缺陷小鼠培养基中的HA降低，新生内膜增生受到强烈抑制。然而，内侧和腔内区域未受影响。细胞密度、增殖和凋亡未发生改变，表明细胞数量和细胞外基质均成比例减少。此外，通过乙酰胆碱诱导的主动脉环松弛和内皮一氧化氮合酶免疫印迹测定的内皮功能和动脉血压不受影响。此外，根据主动脉总蛋白提取物的测定，氧化应激反应不受影响。对比对照和结扎颈动脉的转录组分析提示，在与VSMC迁移相关的结扎反应中，has3缺陷小鼠的各种信号通路的差异调节有所减轻，包括局灶粘连、整合素、MAPK和磷脂酰肌醇信号系统。体外实验中，慢病毒在血管平滑肌细胞（VSMC）中过表达HAS3支持血管平滑肌细胞响应PDGF-BB的迁移表型。因此，敲低HAS3降低了PDGF-BB的迁移反应，并降低了PDGF-B mRNA的表达。血管损伤后，has3介导的HA合成支持精液信号通路激活VSMC，增加pdgf - bb介导的迁移，进而促进体内新生内膜增生。
Hyaluronan (HA) is a polymeric glucosaminoglycan that forms a provisional extracellular matrix in diseased vessels. HA is synthesized by three different HA-synthases (HAS1, -2, -3). Aim of this study was to unravel the role of the HAS3 isoenzyme during experimental neointimal hyperplasia. Neointimal hyperplasia was induced in Has3-deficient mice by ligation of the carotid artery. HA in the media of Has3-deficient mice was decreased 28 days after ligation and neointimal hyperplasia was strongly inhibited. However, medial and luminal areas were unaffected. Cell density, proliferation, and apoptosis were not altered, suggesting a proportional decrease of both the number of cells and extracellular matrix. In addition, endothelial function as determined by acetylcholine-induced relaxation of aortic rings and immunoblotting of endothelial nitric oxide synthase and arterial blood pressure were not affected. Furthermore, the oxidative stress response was not affected as determined in total protein extracts from aortae. Transcriptome analysis comparing control versus ligated carotid arteries hinted towards a mitigated differential regulation of various signaling pathways in Has3-deficient mice in response to ligation that were related to VSMC migration including focal adhesions, integrins, MAPK, and phosphatidylinositol signaling system. Lentiviral overexpression of HAS3 in vascular smooth muscle cells (VSMC) supported the migratory phenotype of VSMC in response to PDGF-BB in vitro. Accordingly, knock down of HAS3 reduced the migratory response to PDGF-BB and in addition decreased the expression of PDGF-B mRNA. HAS3-mediated HA synthesis after vessel injury supports seminal signaling pathways in activation of VSMC, increases PDGF-BB-mediated migration, and in turn enhances neointimal hyperplasia in vivo.