Local angiogenic interplay of Vegfc/d and Vegfa controls brain region-specific emergence of fenestrated capillaries.
Local angiogenic interplay of Vegfc/d and Vegfa controls brain region-specific emergence of fenestrated capillaries.
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DOI：
10.7554/elife.86066
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发表时间：
2023-05-16
期刊：
影响因子：
7.7
通讯作者：
Matsuoka RL
中科院分区：
文献类型：
--
作者：
Parab S;Card OA;Chen Q;America M;Buck LD;Quick RE;Horrigan WF;Levkowitz G;Vanhollebeke B;Matsuoka RL
有孔和血脑屏障（BBB）形成内皮细胞构成主要的脑毛细血管，这种血管异质性对区域特异性神经功能和脑稳态至关重要。这些毛细血管类型如何以脑区域特异性方式出现并随后建立脑内血管异质性仍不清楚。在这里，我们进行了比较分析血管化的斑马鱼脉络丛（CP），脑室周围器官（CVOs），和视网膜脉络膜，并显示共同的血管生成机制的开窗脑毛细血管形成的关键。我们发现Gpr 124、Reck或Wnt 7aa缺陷的斑马鱼表现出严重受损的BBB血管生成，而在CP、CVOs和视网膜脉络膜中的有孔毛细血管形成没有任何明显缺陷。相反，各种VEGF组合的遗传丢失导致这些器官的Wnt 7/Gpr 124/Reck信号独立血管化的显著破坏。表型变异和特异性揭示了CP和CVO血管化过程中Vegfs依赖性血管生成的异质性内皮需求，确定了Vegfc/d和Vegfa在此过程中的意外相互作用。从机制上讲，表达分析和旁分泌活性缺陷型vegfc突变体表征表明，CP和CVO中存在的内皮细胞和非神经元特化细胞类型是负责区域限制性血管生成相互作用的Vegfs的主要来源。因此，脑区域特异性的呈现和Vegfc/d和Vegfa的相互作用控制了有孔毛细血管的出现，提供了对驱动脑内血管异质性和其他器官中有孔血管形成的机制的深入了解。
Fenestrated and blood-brain barrier (BBB)-forming endothelial cells constitute major brain capillaries, and this vascular heterogeneity is crucial for region-specific neural function and brain homeostasis. How these capillary types emerge in a brain region-specific manner and subsequently establish intra-brain vascular heterogeneity remains unclear. Here, we performed a comparative analysis of vascularization across the zebrafish choroid plexuses (CPs), circumventricular organs (CVOs), and retinal choroid, and show common angiogenic mechanisms critical for fenestrated brain capillary formation. We found that zebrafish deficient for Gpr124, Reck, or Wnt7aa exhibit severely impaired BBB angiogenesis without any apparent defect in fenestrated capillary formation in the CPs, CVOs, and retinal choroid. Conversely, genetic loss of various Vegf combinations caused significant disruptions in Wnt7/Gpr124/Reck signaling-independent vascularization of these organs. The phenotypic variation and specificity revealed heterogeneous endothelial requirements for Vegfs-dependent angiogenesis during CP and CVO vascularization, identifying unexpected interplay of Vegfc/d and Vegfa in this process. Mechanistically, expression analysis and paracrine activity-deficient vegfc mutant characterization suggest that endothelial cells and non-neuronal specialized cell types present in the CPs and CVOs are major sources of Vegfs responsible for regionally restricted angiogenic interplay. Thus, brain region-specific presentations and interplay of Vegfc/d and Vegfa control emergence of fenestrated capillaries, providing insight into the mechanisms driving intra-brain vascular heterogeneity and fenestrated vessel formation in other organs.
影响因子：
4.7
作者：
Le YZ;Bai Y;Zhu M;Zheng L
通讯作者：
Zheng L