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Cited by 93Cell Adhesion Molecules ResearchSepsis Diagnosis and TreatmentBarrier Structure and Function Studies

Absence of Integrin αvβ3 Enhances Vascular Leak in Mice by Inhibiting Endothelial Cortical Actin Formation

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Su, George, Atakilit, Amha, Li, John T., Wu, Nanyan, Bhattacharya, Mallar, Zhu, Jieling, Shieh, Jennifer E., Li, Elizabeth +4 more·2012·American Journal of Respiratory and Critical Care Medicine
DOI 10.1164/rccm.201108-1381ocPMC PMC3262039
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Abstract

Rationale: Sepsis and acute lung injury (ALI) have devastatingly high mortality rates. Both are associated with increased vascular leak, a process regulated by complex molecular mechanisms. Objectives: We hypothesized that integrin αvβ3 could be an important determinant of vascular leak and endothelial permeability in sepsis and ALI. Methods: β3 subunit knockout mice were tested for lung vascular leak after endotracheal LPS, and systemic vascular leak and mortality after intraperitoneal LPS and cecal ligation and puncture. Possible contributory effects of β3 deficiency in platelets and other hematopoietic cells were excluded by bone marrow reconstitution experiments. Endothelial cells treated with αvβ3 antibodies were evaluated for sphingosine-1 phosphate (S1P)–mediated alterations in barrier function, cytoskeletal arrangement, and integrin localization. Measurements and Main Results: β3 knockout mice had increased vascular leak and pulmonary edema formation after endotracheal LPS, and increased vascular leak and mortality after intraperitoneal LPS and cecal ligation and puncture. In endothelial cells, αvβ3 antibodies inhibited barrier-enhancing and cortical actin responses to S1P. Furthermore, S1P induced translocation of αvβ3 from discrete focal adhesions to cortically distributed sites through Gi- and Rac1-mediated pathways. Cortical αvβ3 localization after S1P was decreased by αvβ3 antibodies, suggesting that ligation of the αvβ3 with its extracellular matrix ligands is required to stabilize cortical αvβ3 focal adhesions. Conclusions: Our studies identify a novel mechanism by which αvβ3 mitigates increased vascular leak, a pathophysiologic function central to sepsis and ALI. These studies suggest that drugs designed to block αvβ3 may have the unexpected side effect of intensifying sepsis- and ALI-associated vascular endothelial leak.

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Crossref · 10.1164/rccm.201108-1381oc

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  • Integrin-mediated EC adhesion to the vascular basement membrane mediates vascular stability and angiogenesis.

    “Collectively, integrin-mediated EC adhesion to the vascular basement membrane is known to mediate vascular stability and angiogenesis (9, 10), but less is known about the regulation of integrin-coupled EC adhesions during vascular leakage in mature vessels.”

    From Targeting β1-integrin inhibits vascular leakage in endotoxemia (2018) · cites this paper as [9]

    The Abstract says integrins participate in endothelial barrier function, and the Discussion identifies αvβ3 as a regulator of vascular barrier resistance. The cited paper does not establish that endothelial adhesion specifically to the vascular basement membrane mediates angiogenesis; its Discussion says αvβ3 is not thought to regulate normal blood vessel development and function. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • αv- or β3-integrin silencing results in increased stress fibre formation and loss of endothelial cortical actin cytoskeleton.

    “We found that αv- or β3-integrin silencing resulted in increased stress fibre formation and loss of endothelial cortical actin cytoskeleton, in line with previous results39.”

    From Endothelial destabilization by angiopoietin-2 via integrin β1 activation (2015) · cites this paper as [39]

    The Results (page unavailable) report that αvβ3-blocking antibodies disrupted S1P-induced cortical actin and seemed to increase actin stress fibres in endothelial cells. This supports a similar phenotype, but the paper tested antibody blockade rather than αv- or β3-integrin silencing, and describes the stress-fibre increase tentatively. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • β3-integrin silencing decreases VE-cadherin in BECs.

    “By contrast, β3-integrin (shβ3) silencing decreased VE-cadherin in BECs, in line with previous studies (9, 15), and shβ3 did not prevent the thrombin-induced loss of VE-cadherin (Fig. 2 C and D and SI Appendix, Fig. S3A).”

    From Targeting β1-integrin inhibits vascular leakage in endotoxemia (2018) · cites this paper as [9]

    The Results report that αvβ3-blocking antibodies increased agonist-induced permeability in human endothelial cells, but do not report β3 silencing in BECs or a decrease in VE-cadherin. Searches for VE-cadherin and cadherin found no passage addressing that outcome. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 1

  1. [30]Max R, Gerritsen RR, Nooijen PT, Goodman SL, Sutter A, Keilholz U, Ruiter DJ, De Waal RM. Immunohistochemical analysis of integrin alpha vbeta3 expression on tumor-associated vessels of human carcinomas. Int J Cancer 1997;71:320–324 [DOI] [PubMed] [Google Scholar]

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Authors
Su, G., Atakilit, A., Li, J. T., Wu, N., Bhattacharya, M., Zhu, J., Shieh, J. E., Li, E., Chen, R., Sun, S., Su, C. P., & Sheppard, D.
Affiliations
University of California, San Francisco (US)
Corresponding author
Su, George
ORCID
Venue
American Journal of Respiratory and Critical Care Medicine
Publisher
Oxford University Press (OUP)
Published
2012-01-01
Volume
185
Issue
1
Pages
58-66
ISSN
  • 1073-449X (ISSN-L)
  • 1535-4970
DOI
10.1164/rccm.201108-1381oc
PMC
PMC3262039
OpenAlex
W2065965568
Cited by
92
References
58
Citations by year
2026: 2 · 2025: 8 · 2024: 3 · 2023: 5 · 2022: 4 · 2021: 12 · 2020: 10 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 7 · 2015: 11 · 2014: 6 · 2013: 7 · 2012: 4
FWCI
4.32
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • American Journal of Respiratory and Critical Care Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (R01HL083950, K08HL083097, HL083950)
Topics
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
integrin αvβ3, vascular leakage, endothelial permeability, acute lung injury, sepsis, sphingosine-1-phosphate, endothelial barrier function, cortical actin, focal adhesions, Rac1, Gi protein, cecal ligation and puncture, lipopolysaccharide, pulmonary edema
MeSH terms
Actins, Animals, Disease Models, Animal, Endothelium, Vascular, Female, Lysophospholipids, Pulmonary Edema, Sphingosine, Vascular Diseases, Signal Transduction, Mice, Knockout, Sepsis, Integrin alphaVbeta3, Mice, Acute Lung Injury

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