Regulation of Vegf signaling by natural and synthetic ligands

Rossi, Andrea; Gauvrit, Sébastien; Marass, Michele; Pan, Lingai; Moens, Cecilia B.; Stainier, Didier Y. R.

doi:10.1182/blood-2016-04-711192

Cited by 56 publications

(55 citation statements)

References 29 publications

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“…Zebrafish Vegfd is capable of rescuing Vegfaa zebrafish mutants (Rossi et al, 2016), which strongly supports our data and together suggests that Vegfd can activate signaling downstream of Kdr. As mouse Vegfd does not bind to Vegfr2 but the human protein does (Baldwin et al, 2001a), zebrafish may present a very useful alternative model for studying the function of VEGFD/VEGFR2 signaling.…”

Section: Discussion a Role For Vegfd In Developmental Angiogenesis Ansupporting

confidence: 78%

Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development

et al. 2017

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Vascular endothelial growth factors (VEGFs) control angiogenesis and lymphangiogenesis during development and in pathological conditions. In the zebrafish trunk, Vegfa controls the formation of intersegmental arteries by primary angiogenesis and Vegfc is essential for secondary angiogenesis, giving rise to veins and lymphatics. Vegfd has been largely thought of as dispensable for vascular development in vertebrates. Here, we generated a zebrafish vegfd mutant by genome editing. vegfd mutants display significant defects in facial lymphangiogenesis independent of vegfc function. Strikingly, we find that vegfc and vegfd cooperatively control lymphangiogenesis throughout the embryo, including during the formation of the trunk lymphatic vasculature. Interestingly, we find that vegfd and vegfc also redundantly drive artery hyperbranching phenotypes observed upon depletion of Flt1 or Dll4. Epistasis and biochemical binding assays suggest that, during primary angiogenesis, Vegfd influences these phenotypes through Kdr (Vegfr2) rather than Flt4 (Vegfr3). These data demonstrate that, rather than being dispensable during development, Vegfd plays context-specific indispensable and also compensatory roles during both blood vessel angiogenesis and lymphangiogenesis.

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Section: Discussion a Role For Vegfd In Developmental Angiogenesis Ansupporting

confidence: 78%

Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development

et al. 2017

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“…S5A). Therefore, vegfab bns92 is likely to be a severe or even a null allele (25). By carefully analyzing VTA formation in vegfaa bns1 , vegfab bns92 , and vegfc hu6410 mutant animals, we found that the vegfab bns92 mutants show a fully penetrant loss of VTA phenotype, as observed in radial glia-ablated fish (Fig.…”

Section: Vtas Are Important For Subsequent Vascularization Around Andmentioning

confidence: 59%

“…VTA formation was not rescued by other Vegfs, such as Vegfaa, in the absence of Vegfab (Fig. S6 D and F), possibly because Vegfaa and Vegfab appear to have different properties (25). The Vegf decoy receptor sFlt1 was recently shown to limit the oversprouting of the dorsal ISVs around the spinal cord during early larval stages (3-6 dpf) (14,26).…”

Section: Discussionmentioning

confidence: 97%

“…We recently generated and characterized vegfaa bns1 mutants that exhibit severe vasculogenesis and angiogenesis defects, leading to a lack of blood circulation, pericardial edema, and early larval death (24,25). In addition, we generated a vegfab bns92 mutant allele by targeted genome editing using the CRISPR/Cas9 system (25) lost, thus affecting Vegf dimerization and function (25) (Fig.…”

Section: Vtas Are Important For Subsequent Vascularization Around Andmentioning

confidence: 99%

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CNS-resident progenitors direct the vascularization of neighboring tissues

Matsuoka

Rossi

Stone

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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...

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“…To further explore the role of vegfaa in heart regeneration, we took advantage of a recently generated vegfaa mutant (28). vegfaa −/− embryos display severe angiogenic defects from an early stage (29). To raise these mutants to adulthood, we rescued them by injecting vegfaa 121 or vegfaa 165 mRNA at the one-cell stage.…”

Section: Resultsmentioning

confidence: 99%

Fast revascularization of the injured area is essential to support zebrafish heart regeneration

Marín-Juez

Marass

Gauvrit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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158

222

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Zebrafish have a remarkable capacity to regenerate their heart. Efficient replenishment of lost tissues requires the activation of different cell types including the epicardium and endocardium. A complex set of processes is subsequently needed to support cardiomyocyte repopulation. Previous studies have identified important determinants of heart regeneration; however, to date, how revascularization of the damaged area happens remains unknown. Here, we show that angiogenic sprouting into the injured area starts as early as 15 h after injury. To analyze the role of vegfaa in heart regeneration, we used vegfaa mutants rescued to adulthood by vegfaa mRNA injections at the one-cell stage. Surprisingly, vegfaa mutants develop coronaries and revascularize after injury. As a possible explanation for these observations, we find that vegfaa mutant hearts up-regulate the expression of potentially compensating genes. Therefore, to overcome the lack of a revascularization phenotype in vegfaa mutants, we generated fish expressing inducible dominant negative Vegfaa. These fish displayed minimal revascularization of the damaged area. In the absence of fast angiogenic revascularization, cardiomyocyte proliferation did not occur, and the heart failed to regenerate, retaining a fibrotic scar. Hence, our data show that a fast endothelial invasion allows efficient revascularization of the injured area, which is necessary to support replenishment of new tissue and achieve efficient heart regeneration. These findings revisit the model where neovascularization is considered to happen concomitant with the formation of new muscle. Our work also paves the way for future studies designed to understand the molecular mechanisms that regulate fast revascularization.heart regeneration | angiogenesis | revascularization | coronaries | VEGF

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Regulation of Vegf signaling by natural and synthetic ligands

Cited by 56 publications

References 29 publications

Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development

Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development

CNS-resident progenitors direct the vascularization of neighboring tissues

Fast revascularization of the injured area is essential to support zebrafish heart regeneration

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