CNS-resident progenitors direct the vascularization of neighboring tissues

Abstract

Organ growth requires the coordinated invasion and expansion of blood vessel networks directed by tissue-resident cells and morphogenetic cues. A striking example of this intercellular communication is the vascularization of the central nervous system (CNS), which is driven by neuronal progenitors, including neuroepithelial cells and radial glia. Although the importance of neuronal progenitors in vascular development within the CNS is well recognized, how these progenitors regulate the vasculature outside the CNS remains largely unknown. Here we show that CNS-resident radial glia direct the vascularization of neighboring tissues during development. We find that genetic ablation of radial glia in zebrafish larvae leads to a complete loss of the bilateral vertebral arteries (VTAs) that extend along the ventrolateral sides of the spinal cord. Importantly, VTA formation is not affected by ablation of other CNS cell types, and radial glia ablation also compromises the subsequent formation of the peri-neural vascular plexus (PNVP), a vascular network that surrounds the CNS and is critical for CNS angiogenesis. Mechanistically, we find that radial glia control these processes via Vegfab/Vegfr2 signaling: vegfab is expressed by radial glia, and genetic or pharmacological inhibition of Vegfab/Vegfr2 signaling blocks the formation of the VTAs and subsequently of the PNVP. Moreover, mosaic overexpression of Vegfab in radial glia is sufficient to partially rescue the VTA formation defect in vegfab mutants. Thus, our findings identify a critical function for CNSresident progenitors in the regulation of vascularization outside the CNS, serving as a paradigm for cross-tissue coordination of vascular morphogenesis and growth.angiogenesis | spinal cord | zebrafish | radial glia | Vegf signaling T he vascular system functions in the delivery of oxygen, nutrients, and hormones, thereby providing fundamental support for tissue growth, homeostasis, and function. During development, the vascularization of the central nervous system (CNS) initiates by angiogenic sprouting from the peri-neural vascular plexus (PNVP) into neural tissues (1-4). This angiogenic sprouting event is directed primarily by morphogenetic cues that derive from CNS-resident cells. Neuronal progenitors, including neuroepithelial cells and radial glia, secrete factors, including Wnts and Vegfs, which promote the ingression of blood vessels into neural tissues (5-9). The metabolic state of neurons (10, 11) as well as signals from specialized CNS glia (12, 13) also play instructive roles in vascular patterning in the developing CNS. In contrast to these recent advances in our understanding of CNS vascularization, however, the cellular and molecular bases of vascular assembly around the CNS remain poorly understood.We have recently begun to investigate the role of different CNS cell types in vascular development around the CNS by optimizing genetic ablation conditions for these cell types in zebrafish (14). This ablation method uses the bacterial enzyme Nitroreductase...

Pituicyte Cues Regulate the Development of Permeable Neuro-Vascular Interfaces

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Endothelial and non-endothelial responses to estrogen excess during development lead to vascular malformations

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