Apelin signaling drives vascular endothelial cells towards a pro-angiogenic state
- Philipps-University Marburg, Germany
- Max Planck Institute for Heart and Lung Research, Germany
- University of Muenster, Germany
Abstract
To form new blood vessels (angiogenesis), endothelial cells (ECs) must be activated and acquire highly migratory and proliferative phenotypes. However, the molecular mechanisms that govern these processes are incompletely understood. Here, we show that Apelin signaling functions to drive ECs into such an angiogenic state. Zebrafish lacking Apelin signaling exhibit defects in endothelial tip cell morphology and sprouting. Using transplantation experiments, we find that in mosaic vessels, wild-type ECs leave the dorsal aorta (DA) and form new vessels while neighboring ECs defective in Apelin signaling remain in the DA. Mechanistically, Apelin signaling enhances glycolytic activity in ECs at least in part by increasing levels of the growth-promoting transcription factor c-Myc. Moreover, Apelin expression is regulated by Notch signaling, and its function is required for the hypersprouting phenotype in Delta-like 4 (Dll4) knockdown embryos. These data provide new insights into fundamental principles of blood vessel formation and Apelin signaling, enabling a better understanding of vascular growth in health and disease.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Christian SM Helker
Didier YR Stainier
Funding
Deutsche Forschungsgemeinschaft (SFB 834)
- Didier YR Stainier
North Rhine-Westphalia (return fellowship')
- Wiebke Herzog
Deutsche Forschungsgemeinschaft (SFB 834)
- Christian SM Helker
Deutsche Forschungsgemeinschaft (GRK2213)
- Christian SM Helker
Deutsche Forschungsgemeinschaft (GRK2213)
- Jean Eberlein
Deutsche Forschungsgemeinschaft (GRK2213)
- Julian Malchow
Deutsche Forschungsgemeinschaft (HE4585/3-1)
- Wiebke Herzog
H2020 European Research Council (EMERGE (773047))
- Michael Potente
Deutsche Forschungsgemeinschaft (EXC 2026)
- Michael Potente
H2020 European Research Council (AdG project: ZMOD 694455)
- Didier YR Stainier
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Caroline E Burns, Boston Children's Hospital, United States
Ethics
Animal experimentation: Ethics StatementAll zebrafish husbandry was performed under standard conditions, and all experiments were conducted in accordance with institutional (MPG) and national ethical and animal welfare guidelines (Proposal numbers: B2/1017, B2/1041, B2/1218, B2/1138). All procedures conform to the guidelines from Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes.
Version history
- Received: January 29, 2020
- Accepted: September 19, 2020
- Accepted Manuscript published: September 21, 2020 (version 1)
- Version of Record published: October 16, 2020 (version 2)
Copyright
© 2020, Helker et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Apelin signaling drives vascular endothelial cells towards a pro-angiogenic state
eLife 9:e55589.
https://doi.org/10.7554/eLife.55589
Further reading
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We previously showed that SerpinE2 and the serine protease HtrA1 modulate fibroblast growth factor (FGF) signaling in germ layer specification and head-to-tail development of Xenopus embryos. Here, we present an extracellular proteolytic mechanism involving this serpin-protease system in the developing neural crest (NC). Knockdown of SerpinE2 by injected antisense morpholino oligonucleotides did not affect the specification of NC progenitors but instead inhibited the migration of NC cells, causing defects in dorsal fin, melanocyte, and craniofacial cartilage formation. Similarly, overexpression of the HtrA1 protease impaired NC cell migration and the formation of NC-derived structures. The phenotype of SerpinE2 knockdown was overcome by concomitant downregulation of HtrA1, indicating that SerpinE2 stimulates NC migration by inhibiting endogenous HtrA1 activity. SerpinE2 binds to HtrA1, and the HtrA1 protease triggers degradation of the cell surface proteoglycan Syndecan-4 (Sdc4). Microinjection of Sdc4 mRNA partially rescued NC migration defects induced by both HtrA1 upregulation and SerpinE2 downregulation. These epistatic experiments suggest a proteolytic pathway by a double inhibition mechanism:
SerpinE2 ┤HtrA1 protease ┤Syndecan-4 → NC cell migration.
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Human fetal development has been associated with brain health at later stages. It is unknown whether growth in utero, as indexed by birth weight (BW), relates consistently to lifespan brain characteristics and changes, and to what extent these influences are of a genetic or environmental nature. Here we show remarkably stable and lifelong positive associations between BW and cortical surface area and volume across and within developmental, aging and lifespan longitudinal samples (N = 5794, 4–82 y of age, w/386 monozygotic twins, followed for up to 8.3 y w/12,088 brain MRIs). In contrast, no consistent effect of BW on brain changes was observed. Partly environmental effects were indicated by analysis of twin BW discordance. In conclusion, the influence of prenatal growth on cortical topography is stable and reliable through the lifespan. This early-life factor appears to influence the brain by association of brain reserve, rather than brain maintenance. Thus, fetal influences appear omnipresent in the spacetime of the human brain throughout the human lifespan. Optimizing fetal growth may increase brain reserve for life, also in aging.
