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The vascular gene Apold1 is dispensable for normal development but controls angiogenesis under pathological conditions


Fan, Zheng; Ardicoglu, Raphaela; Batavia, Aashil A; Rust, Ruslan; von Ziegler, Lukas; Waag, Rebecca; Zhang, Jing; Desgeorges, Thibaut; Sturman, Oliver; Dang, Hairuo; Weber, Rebecca; Roszkowski, Martin; Moor, Andreas E; Schwab, Martin E; Germain, Pierre-Luc; Bohacek, Johannes; De Bock, Katrien (2023). The vascular gene Apold1 is dispensable for normal development but controls angiogenesis under pathological conditions. Angiogenesis, 26(3):385-407.

Abstract

The molecular mechanisms of angiogenesis have been intensely studied, but many genes that control endothelial behavior and fate still need to be described. Here, we characterize the role of Apold1 (Apolipoprotein L domain containing 1) in angiogenesis in vivo and in vitro. Single-cell analyses reveal that - across tissues - the expression of Apold1 is restricted to the vasculature and that Apold1 expression in endothelial cells (ECs) is highly sensitive to environmental factors. Using Apold1$^{-/-}$ mice, we find that Apold1 is dispensable for development and does not affect postnatal retinal angiogenesis nor alters the vascular network in adult brain and muscle. However, when exposed to ischemic conditions following photothrombotic stroke as well as femoral artery ligation, Apold1$^{-/-}$ mice display dramatic impairments in recovery and revascularization. We also find that human tumor endothelial cells express strikingly higher levels of Apold1 and that Apold1 deletion in mice stunts the growth of subcutaneous B16 melanoma tumors, which have smaller and poorly perfused vessels. Mechanistically, Apold1 is activated in ECs upon growth factor stimulation as well as in hypoxia, and Apold1 intrinsically controls EC proliferation but not migration. Our data demonstrate that Apold1 is a key regulator of angiogenesis in pathological settings, whereas it does not affect developmental angiogenesis, thus making it a promising candidate for clinical investigation.

Abstract

The molecular mechanisms of angiogenesis have been intensely studied, but many genes that control endothelial behavior and fate still need to be described. Here, we characterize the role of Apold1 (Apolipoprotein L domain containing 1) in angiogenesis in vivo and in vitro. Single-cell analyses reveal that - across tissues - the expression of Apold1 is restricted to the vasculature and that Apold1 expression in endothelial cells (ECs) is highly sensitive to environmental factors. Using Apold1$^{-/-}$ mice, we find that Apold1 is dispensable for development and does not affect postnatal retinal angiogenesis nor alters the vascular network in adult brain and muscle. However, when exposed to ischemic conditions following photothrombotic stroke as well as femoral artery ligation, Apold1$^{-/-}$ mice display dramatic impairments in recovery and revascularization. We also find that human tumor endothelial cells express strikingly higher levels of Apold1 and that Apold1 deletion in mice stunts the growth of subcutaneous B16 melanoma tumors, which have smaller and poorly perfused vessels. Mechanistically, Apold1 is activated in ECs upon growth factor stimulation as well as in hypoxia, and Apold1 intrinsically controls EC proliferation but not migration. Our data demonstrate that Apold1 is a key regulator of angiogenesis in pathological settings, whereas it does not affect developmental angiogenesis, thus making it a promising candidate for clinical investigation.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > Neuroscience Center Zurich
07 Faculty of Science > Institute of Molecular Life Sciences
04 Faculty of Medicine > Institute for Regenerative Medicine (IREM)
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Physiology
Life Sciences > Clinical Biochemistry
Life Sciences > Cancer Research
Language:English
Date:August 2023
Deposited On:12 Apr 2023 08:30
Last Modified:30 May 2024 01:40
Publisher:Springer
ISSN:0969-6970
OA Status:Hybrid
Publisher DOI:https://doi.org/10.1007/s10456-023-09870-z
PubMed ID:36933174
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)