Flt1 at the neuro-vascular interface

Flt1 位于神经血管界面

• 批准号: 289490867
• 负责人: Professor Dr. Ferdinand Le Noble
• 金额: --
• 依托单位: Abteilung für Zell- und Entwicklungsbiologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/289490867?language=en
• 关键词: Flt1; neuro; vascular; interface

The vascular network closely associates with the neuronal network throughout embryonic development, in adulthood and during tissue regeneration. Close association of vessels and neuronal networks allows reciprocal cross-talk involving diffusible molecules, which is important for physiological functions in both domains. Disturbances herein associate with neurodegenerative diseases, neuropathy, and cardiovascular disorders.Formation of vascular and neuronal networks shows many similarities including common molecular cues and the principle of directed guidance. In the vascular system, Vegf-a acts as the major regulator of angiogenesis and sprout guidance. In the neuronal system, Vegf-a can have direct effects on neurons and modulate processes such as neuronal survival and axon guidance. Vegf receptor-1 (Flt1) mainly acts as a Vegf-a decoy receptor, thereby limiting Vegf-a bio-availability and signaling through Vegf receptor-2 (Kdr). Flt1 is expressed in both vessels and nerves and therefor uniquely endowed with the dual ability to affect growth of vessels and nerves. We hypothesize that Flt1 plays a central role in neuro-vascular communication. In line with this hypothesis we found that spinal cord vascularization in zebrafish proceeds from veins involving two-tiered regulation of neuronal soluble Flt1 (sFlt1) and Vegfaa via a novel sprouting mode termed tertiary sprouting. Here we propose to analyze the molecular mechanism driving tertiary sprout initiation, sprout guidance and the selective anastomosis formation with arteries. Pilot data suggest that tertiary sprouts sample their targets and preferentially anastomose with Neuropilin-1 (Nrp1) expressing endothelium in specific arterial domains. Mechanistically, neuronal Plgf acts as a positive regulator of this process. Plgf provokes displacement of Vegfaa from arterial Nrp1, thereby augmenting Vegfaa around arteries, promoting arterial Kdrl signaling and filopodia formation, an endothelial feature that critically determines the propensity to form an anastomosis.During spinal cord development, stem and progenitor cells differentiate into mature neurons, a process that is paralleled by a change from glycolytic toward more aerobic tissue metabolism, and increased vascularization. Here we propose to analyze how the extent of spinal cord vascularization controls the switch of stem cell expansion to differentiation either via changes in metabolism or angiocrine signals. To test this we created a series of transgenic and mutant zebrafish with either hyper vascularized or hypo vascularized spinal cords based on modulation of sFlt1 and Vegfaa levels at the neuro-vascular interface. Using single cell sequencing and RNA tomo-seq we will track changes in cell fate specification in a spatio-temporal manner. Preliminary data show reduced progenitor pools in the hyper vascularization scenarios, consistent with blood vessel function determining neuronal differentiation.

在胚胎发育、成年期和组织再生过程中，血管网络与神经元网络密切相关。血管和神经网络的紧密联系使得扩散分子的相互串扰成为可能，这对两个领域的生理功能都是重要的。此处的干扰与神经退行性疾病、神经病变和心血管疾病有关。血管网络和神经网络的形成有许多相似之处，包括共同的分子线索和定向引导原理。在血管系统中，Vegf-a是血管生成和引导发芽的主要调节因子。在神经系统中，Vegf-a可以直接作用于神经元，调节神经元存活和轴突引导等过程。Vegf受体-1 （Flt1）主要作为Vegf-a诱饵受体，从而限制Vegf-a的生物利用度和通过Vegf受体-2 （Kdr）的信号传导。Flt1在血管和神经中均有表达，因此具有独特的影响血管和神经生长的双重能力。我们假设Flt1在神经血管通讯中起着核心作用。根据这一假设，我们发现斑马鱼的脊髓血管化是通过一种新的称为三级发芽的发芽模式，通过涉及神经元可溶性Flt1 （sFlt1）和Vegfaa的两层调控的静脉进行的。在此，我们拟从分子机制上分析驱动三级萌芽形成、萌芽引导和与动脉选择性吻合形成的机制。初步数据表明，三级芽在特定的动脉区域取样并优先与表达内皮的Neuropilin-1 （Nrp1）吻合。从机制上讲，神经元Plgf对这一过程起着积极的调节作用。Plgf刺激Vegfaa从动脉Nrp1位移，从而增加动脉周围的Vegfaa，促进动脉Kdrl信号传导和丝状足形成，这是一种内皮特征，关键决定了形成吻合的倾向。在脊髓发育过程中，干细胞和祖细胞分化为成熟的神经元，这一过程与糖酵解向更多有氧组织代谢和血管化增加的变化相平行。在这里，我们建议分析脊髓血管化的程度如何通过代谢或血管分泌信号的变化来控制干细胞扩增到分化的开关。为了验证这一点，我们基于神经-血管界面sFlt1和Vegfaa水平的调节，创造了一系列具有高血管化或低血管化脊髓的转基因和突变斑马鱼。利用单细胞测序和RNA tomo-seq，我们将以时空方式跟踪细胞命运规范的变化。初步数据显示，在过度血管化的情况下，祖细胞池减少，与血管功能决定神经元分化一致。