Functional Importance of a Proteoglycan Coreceptor in Pathologic Lymphangiogenesis.
Functional Importance of a Proteoglycan Coreceptor in Pathologic Lymphangiogenesis.
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DOI：
10.1161/circresaha.116.308504
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发表时间：
2016-07-08
影响因子：
20.1
通讯作者：
Fuster MM
中科院分区：
文献类型：
--
作者：
Johns SC;Yin X;Jeltsch M;Bishop JR;Schuksz M;El Ghazal R;Wilcox-Adelman SA;Alitalo K;Fuster MM
补充数字内容可在文本中找到。淋巴管生长由主要的促淋巴管生成因子介导，如血管内皮生长因子（VEGF-C）和VEGF-D以及其他内皮效应物。硫酸乙酰肝素是一种线性多糖，表达在细胞膜和基质上的蛋白聚糖核心蛋白上，在血管生成中发挥作用，尽管对体内淋巴重塑中的任何功能知之甚少。探讨硫酸乙酰肝素蛋白多糖介导病理性淋巴管重塑的遗传学基础和机制。在病理模型中，主要硫酸乙酰肝素生物合成酶N-脱乙酰基酶/N-磺基转移酶-1（Ndst 1;参与聚糖链硫酸化）的淋巴管内皮缺陷与淋巴管生成减少相关，包括自发性肿瘤形成。小鼠突变体表现出肿瘤相关的淋巴管与凋亡细胞核。突变的淋巴内皮细胞表现出有丝分裂原（Erk）和生存（Akt）途径信号传导受损，并且VEGF-C介导的对饥饿诱导的细胞凋亡的保护作用降低。淋巴管内皮特异性Ndst 1缺陷（在Ndst 1f/fProx 1 +/CreERT 2小鼠中）足以抑制VEGF-C依赖性淋巴管生成。淋巴硫酸乙酰肝素缺乏减少了对多种VEGF-C物质应答的主要淋巴生长受体VEGF受体-3的磷酸化。Syndecan-4是小鼠淋巴管内皮细胞中主要表达的硫酸乙酰肝素蛋白聚糖，Sdc 4（−/−）小鼠的病理性淋巴管生成受损。在淋巴细胞表面，VEGF-C诱导syndecan-4和VEGF受体-3之间的强关联，其对聚糖破坏敏感。此外，VEGF受体-3丝裂原和生存信号在Ndst 1或Sdc 4缺陷的情况下减少。这些发现表明硫酸乙酰肝素和主要淋巴蛋白聚糖syndecan-4在病理性淋巴重塑中的遗传重要性。这可能会引入新的未来战略，以改变病理性动脉血管重塑。
Supplemental Digital Content is available in the text. Lymphatic vessel growth is mediated by major prolymphangiogenic factors, such as vascular endothelial growth factor (VEGF-C) and VEGF-D, among other endothelial effectors. Heparan sulfate is a linear polysaccharide expressed on proteoglycan core proteins on cell membranes and matrix, playing roles in angiogenesis, although little is known about any function(s) in lymphatic remodeling in vivo. To explore the genetic basis and mechanisms, whereby heparan sulfate proteoglycans mediate pathological lymphatic remodeling. Lymphatic endothelial deficiency in the major heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1; involved in glycan-chain sulfation) was associated with reduced lymphangiogenesis in pathological models, including spontaneous neoplasia. Mouse mutants demonstrated tumor-associated lymphatic vessels with apoptotic nuclei. Mutant lymphatic endothelia demonstrated impaired mitogen (Erk) and survival (Akt) pathway signaling and reduced VEGF-C–mediated protection from starvation-induced apoptosis. Lymphatic endothelial-specific Ndst1 deficiency (in Ndst1f/fProx1+/CreERT2 mice) was sufficient to inhibit VEGF-C–dependent lymphangiogenesis. Lymphatic heparan sulfate deficiency reduced phosphorylation of the major lymphatic growth receptor VEGF receptor-3 in response to multiple VEGF-C species. Syndecan-4 was the dominantly expressed heparan sulfate proteoglycan in mouse lymphatic endothelia, and pathological lymphangiogenesis was impaired in Sdc4(−/−) mice. On the lymphatic cell surface, VEGF-C induced robust association between syndecan-4 and VEGF receptor-3, which was sensitive to glycan disruption. Moreover, VEGF receptor-3 mitogen and survival signaling was reduced in the setting of Ndst1 or Sdc4 deficiency. These findings demonstrate the genetic importance of heparan sulfate and the major lymphatic proteoglycan syndecan-4 in pathological lymphatic remodeling. This may introduce novel future strategies to alter pathological lymphatic-vascular remodeling.