Background Several secreted factors have been identified as drivers of cerebral vasculature development and inducers of blood–brain barrier (BBB) differentiation. Vascular endothelial growth factor A (VEGF-A) is central for driving cerebral angiogenesis and Wnt family factors (Wnt7a, Wnt7b and norrin) are central for induction and maintenance of barrier properties. Expressed by developing neural tissue (neuron and glia progenitors), they influence the formation of central nervous system (CNS) vascular networks. Another type of factors are tissue-specific paracrine factors produced by endothelial cells (ECs), also known as ‘angiocrine’ factors, that provide instructive signals to regulate homeostatic and regenerative processes. Very little is known about CNS angiocrine factors and their role in BBB development. Angiomodulin (AGM) was reported to be expressed by developing vasculature and by pathological tumor vasculature. Here we investigated AGM in the developing CNS and its function as a potential BBB inducer. Methods We analyzed microarray data to identify potential angiocrine factors specifically expressed at early stages of barrier formation. We then tested AGM expression with immunofluorescence and real-time PCR in various organs during development, post-natal and in adults. Permeability induction with recombinant proteins (Miles assay) was used to test potential interaction of AGM with VEGF-A. Results Several angiocrine factors are differentially expressed by CNS ECs and AGM is a prominent CNS-specific angiocrine candidate. Contrary to previous reports, we found that AGM protein expression is specific to developing CNS endothelium and not to highly angiogenic developing vasculature in general. In skin vasculature we found that AGM antagonizes VEGF-A-induced vascular hyperpermeability. Finally, CNS AGM expression is not specific to BBB vasculature and AGM is highly expressed in non-BBB choroid-plexus vasculature. Conclusions We propose AGM as a developmental CNS vascular-specific marker. AGM is not a pan-endothelial marker, nor a general marker for developing angiogenic vasculature. Thus, AGM induction in the developing CNS might be distinct from its induction in pathology. While AGM is able to antagonize VEGF-A-induced vascular hyperpermeability in the skin, its high expression levels in non-BBB CNS vasculature does not support its potential role as a BBB inducer. Further investigation including loss-of-function approaches might elucidate AGM function in the developing CNS.

中文翻译：

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血管调节素 (IGFBP7) 是一种脑特异性血管分泌因子，但可能不是血脑屏障诱导剂

背景 几种分泌因子已被确定为脑血管系统发育的驱动因素和血脑屏障 (BBB) 分化的诱导因子。血管内皮生长因子 A (VEGF-A) 是驱动脑血管生成的核心，Wnt 家族因子（Wnt7a、Wnt7b 和 Norrin）是诱导和维持屏障特性的核心。通过发育神经组织（神经元和神经胶质祖细胞）表达，它们影响中枢神经系统 (CNS) 血管网络的形成。另一种类型的因子是由内皮细胞 (EC) 产生的组织特异性旁分泌因子，也称为“血管分泌”因子，可提供指导信号以调节体内平衡和再生过程。关于 CNS 血管生成因子及其在 BBB 发展中的作用知之甚少。据报道，血管调节蛋白 (AGM) 通过发育的脉管系统和病理性肿瘤脉管系统表达。在这里，我们研究了发育中的 CNS 中的 AGM 及其作为潜在 BBB 诱导剂的功能。方法我们分析了微阵列数据，以确定在屏障形成的早期阶段特异性表达的潜在血管分泌因子。然后，我们在发育、出生后和成人的各个器官中使用免疫荧光和实时 PCR 测试了 AGM 表达。重组蛋白的通透性诱导（Miles 测定）用于测试 AGM 与 VEGF-A 的潜在相互作用。结果 CNS ECs 差异表达了几种血管生成因子，AGM 是一种突出的 CNS 特异性血管生成候选物。与之前的报道相反，我们发现 AGM 蛋白表达对发育中的 CNS 内皮是特异性的，而不是一般来说对高度血管生成的发育中的脉管系统具有特异性。在皮肤脉管系统中，我们发现 AGM 拮抗 VEGF-A 诱导的血管通透性过高。最后，CNS AGM 表达不是 BBB 脉管系统特有的，AGM 在非 BBB 脉络丛脉管系统中高度表达。结论我们建议将 AGM 作为发育中的 CNS 血管特异性标志物。AGM 不是泛内皮标记物，也不是用于发展血管生成脉管系统的通用标记物。因此，发育中的 CNS 中的 AGM 诱导可能与其在病理学中的诱导不同。虽然 AGM 能够拮抗 VEGF-A 诱导的皮肤血管通透性过高，但其在非 BBB CNS 脉管系统中的高表达水平不支持其作为 BBB 诱导剂的潜在作用。