Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain.
Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain.
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DOI：
10.1016/j.devcel.2018.01.018
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发表时间：
2018-03-26
影响因子：
11.8
通讯作者：
Greif DM
中科院分区：
文献类型：
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作者：
Dave JM;Mirabella T;Weatherbee SD;Greif DM
小鼠胚胎血脑屏障（BBB）由内皮细胞（ECs）、周细胞（PCs）和基底膜组成。尽管周细胞对于诱导血管稳定性至关重要，但在血脑屏障发育过程中周细胞内调节内皮细胞形态发生的信号通路仍未被探索。在此，我们发现脑周细胞中缺乏转化生长因子β受体激活素受体样激酶5（Alk5）的小鼠胚胎（突变体）会发生严重的生发基质出血 - 脑室内出血（GMH - IVH）。生发基质（GM）是一种富含神经元和神经胶质前体细胞的高度血管化结构。我们表明突变体的生发基质微血管显示出异常扩张、周细胞覆盖减少、内皮细胞过度增殖、基底膜胶原蛋白减少以及血管周围基质金属蛋白酶活性增强。此外，ALK5缺失的周细胞下调基质金属蛋白酶3组织抑制剂（TIMP3），并且给突变体施用TIMP3可改善内皮细胞形态发生并减轻GMH - IVH。总体而言，我们的研究结果揭示了周细胞ALK5在调节脑内皮细胞形态发生中的关键作用以及TIMP3在GMH - IVH期间的重要治疗潜力。
戴夫等人证明，Pdgfrb - Cre，Alk5（flox/flox）胚胎（突变体）对内皮细胞和生发基质出血（GMH）具有有害的非细胞自主性影响。突变体血管显示出异常扩张、周细胞覆盖减少、内皮细胞过度增殖、胶原蛋白减少以及基质金属蛋白酶活性增强。ALK5缺失的周细胞下调TIMP3，并且施用TIMP3可减轻突变体中的GMH。
The murine embryonic blood-brain barrier (BBB) consists of endothelial cells (ECs), pericytes (PCs) and basement membrane. Although PCs are critical for inducing vascular stability, signaling pathways in PCs that regulate EC morphogenesis during BBB development remain unexplored. Herein, we find that murine embryos lacking the TGFβ receptor activin receptor-like kinase 5 (Alk5) in brain PCs (mutants) develop gross germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH). The germinal matrix (GM) is a highly vascularized structure rich in neuronal and glial precursors. We show that GM microvessels of mutants display abnormal dilation, reduced PC coverage, EC hyperproliferation, reduced basement membrane collagen and enhanced perivascular matrix metalloproteinase activity. Furthermore, ALK5-depleted PCs down-regulate tissue inhibitor of matrix metalloproteinase 3 (TIMP3), and TIMP3 administration to mutants improves endothelial morphogenesis and attenuates GMH-IVH. Overall, our findings reveal a key role for PC ALK5 in regulating brain endothelial morphogenesis and a substantial therapeutic potential for TIMP3 during GMH-IVH. Dave et al. demonstrate that Pdgfrb-Cre, Alk5(flox/flox) embryos (mutants) have deleterious non-cell autonomous effects on endothelial cells and germinal matrix hemorrhage (GMH). Mutant vessels display abnormal dilation, reduced pericyte coverage, endothelial hyperproliferation, reduced collagen and enhanced matrix metalloproteinase activity. ALK5-depleted pericytes down-regulate TIMP3, and TIMP3 administration attenuates GMH in mutants.