Endothelial heterogeneity across distinct vascular beds during homeostasis and inflammation

Abstract

Blood vessels are lined by endothelial cells engaged in distinct organ-specific functions but little is known about their characteristic gene expression profiles. RNA-Sequencing of the brain, lung, and heart endothelial translatome identified specific pathways, transporters and cell-surface markers expressed in the endothelium of each organ, which can be visualized at http://www.rehmanlab.org/ribo. We found that endothelial cells express genes typically found in the surrounding tissues such as synaptic vesicle genes in the brain endothelium and cardiac contractile genes in the heart endothelium. Complementary analysis of endothelial single cell RNA-Seq data identified the molecular signature shared across the endothelial translatome and single cell transcriptomes. The tissue-specific heterogeneity of the endothelium is maintained during systemic in vivo inflammatory injury as evidenced by the distinct responses to inflammatory stimulation. Our study defines endothelial heterogeneity and plasticity and provides a molecular framework to understand organ-specific vascular disease mechanisms and therapeutic targeting of individual vascular beds.

Data availability

RNA Sequencing data have been deposited in GEO under accession code GSE136848We downloaded Tabula Muris data from https://github.com/czbiohub/tabula-muris and Betsholtz Lab data from NCBI Gene Expression Omnibus (GSE99235, GSE98816)

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Ankit Jambusaria

    Department of Pharmacology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Zhigang Hong

    Department of Pharmacology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Lianghui Zhang

    Department of Pharmacology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Shubhi Srivastava

    Department of Pharmacology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Arundhati Jana

    Department of Pharmacology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Peter T Toth

    Department of Pharmacology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Yang Dai

    Department of Bioengineering, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Asrar B Malik

    Department of Pharmacology, University of Illinois at Chicago, Chicago, United States
    For correspondence
    abmalik@uic.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8205-7128
  9. Jalees Rehman

    Department of Pharmacology, University of Illinois at Chicago, Chicago, United States
    For correspondence
    jalees@uic.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2787-9292

Funding

National Institutes of Health (R01HL126516)

  • Jalees Rehman

National Institutes of Health (P01-HL60678)

  • Asrar B Malik
  • Jalees Rehman

National Institutes of Health (T32-HL007829)

  • Asrar B Malik

National Institutes of Health (R01-HL90152)

  • Asrar B Malik
  • Jalees Rehman

American Heart Association (18CDA34110068)

  • Lianghui Zhang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were conducted in accordance with NIH guidelines for the Care and Use of Laboratory Animals and were performed in accordance with protocols approved by the Institutional Animal Care and Use Committees (IACUC) of the University of Illinois (protocol approval numbers 19-014, 13-175 and 16-064) .

Reviewing Editor

  1. Anna Akhmanova, Utrecht University, Netherlands

Publication history

  1. Received: August 27, 2019
  2. Accepted: January 15, 2020
  3. Accepted Manuscript published: January 16, 2020 (version 1)
  4. Version of Record published: February 5, 2020 (version 2)

Copyright

© 2020, Jambusaria 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.

Metrics

  • 9,600
    Page views
  • 1,450
    Downloads
  • 120
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ankit Jambusaria
  2. Zhigang Hong
  3. Lianghui Zhang
  4. Shubhi Srivastava
  5. Arundhati Jana
  6. Peter T Toth
  7. Yang Dai
  8. Asrar B Malik
  9. Jalees Rehman
(2020)
Endothelial heterogeneity across distinct vascular beds during homeostasis and inflammation
eLife 9:e51413.
https://doi.org/10.7554/eLife.51413

Further reading

    1. Immunology and Inflammation
    Rimma Laufer Britva, Aviad Keren ... Amos Gilhar
    Research Article

    Here, we have explored the involvement of innate lymphoid cells-type 1 (ILC1) in the pathogenesis of alopecia areata (AA), because we found them to be significantly increased around lesional and non-lesional HFs of AA patients. To further explore these unexpected findings, we first co-cultured autologous circulating ILC1-like cells (ILC1lc) with healthy, but stressed, organ-cultured human scalp hair follicles (HFs). ILClc induced all hallmarks of AA ex vivo: they significantly promoted premature, apoptosis-driven HF regression (catagen), HF cytotoxicity/dystrophy, and most important for AA pathogenesis, the collapse of the HFs physiological immune privilege. NKG2D-blocking or IFNγ-neutralizing antibodies antagonized this. In vivo, intradermal injection of autologous activated, NKG2D+/IFNγ-secreting ILC1lc into healthy human scalp skin xenotransplanted onto SCID/beige mice sufficed to rapidly induce characteristic AA lesions. This provides the first evidence that ILC1lc, which are positive for the ILC1 phenotype and negative for the classical NK markers, suffice to induce AA in previously healthy human HFs ex vivo and in vivo, and further questions the conventional wisdom that AA is always an autoantigen-dependent, CD8 +T cell-driven autoimmune disease.

    1. Epidemiology and Global Health
    2. Immunology and Inflammation
    Hangjie Zhang, Qianhui Hua ... Huakun Lv
    Research Article

    Background: Although inactivated COVID-19 vaccines are proven to be safe and effective in the general population, the dynamic response and duration of antibodies after vaccination in the real world should be further assessed.

    Methods: We enrolled 1067 volunteers who had been vaccinated with one or two doses of CoronaVac in Zhejiang Province, China. Another 90 healthy adults without previous vaccinations were recruited and vaccinated with three doses of CoronaVac, 28 days and 6 months apart. Serum samples were collected from multiple timepoints and analyzed for specific IgM/IgG and neutralizing antibodies (NAbs) for immunogenicity evaluation. Antibody responses to the Delta and Omicron variants were measured by pseudovirus-based neutralization tests.

    Results: Our results revealed that binding antibody IgM peaked 14-28 days after one dose of CoronaVac, while IgG and NAbs peaked approximately 1 month after the second dose then declined slightly over time. Antibody responses had waned by month 6 after vaccination and became undetectable in the majority of individuals at 12 months. Levels of NAbs to live SARS-CoV-2 were correlated with anti-SARS-CoV-2 IgG and NAbs to pseudovirus, but not IgM. Homologous booster around 6 months after primary vaccination activated anamnestic immunity and raised NAbs 25.5-fold. The neutralized fraction subsequently rose to 36.0% for Delta (p=0.03) and 4.3% for Omicron (p=0.004), and the response rate for Omicron rose from 7.9% (7/89) to 17.8% (16/90).

    Conclusions: Two doses of CoronaVac vaccine resulted in limited protection over a short duration. The inactivated vaccine booster can reverse the decrease of antibody levels to prime strain, but it does not elicit potent neutralization against Omicron; therefore, the optimization of booster procedures is vital.

    Funding: Key Research and Development Program of Zhejiang Province; Key Program of Health Commission of Zhejiang Province/ Science Foundation of National Health Commission; Major Program of Zhejiang Municipal Natural Science Foundation; Explorer Program of Zhejiang Municipal Natural Science Foundation.