uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Perivascular macrophages regulate blood flow following tissue damage
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Show others and affiliations
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Ischemic injuries remain a leading cause of mortality and morbidity world-wide, and restoration of functional blood perfusion is vital to limit tissue damage and support healing. Sterile inflammation is a hallmark of ischemic injury, as macrophages and neutrophils accumulate to clear tissue debris and support vascular regrowth. Here, we delineate the role of macrophages in reestablishment of functional tissue perfusion following ischemic injury and design an immunotherapeutic approach to improve tissue restoration.

Methods: Macrophage-endothelial cell interactions were assessed by intravital microscopy of ischemic hindlimb muscle in CX3CR1GFP/+ mice, and by confocal microscopy of human tissues from amputated legs. Functional muscle perfusion was evaluated as the response to increased local tissue temperature (Δ10°C, heat-induced hyperemia) and measured by Laser Doppler Flowmetry and Laser Speckle Analysis in wild-type and transgenic mice with inducible conditional deletion of inducible nitric oxide synthase (iNOS) in macrophages (Cx3cr1-CreER;Nos2fl/fl, LysM-Cre;Nos2fl/fl). To target restorative functions of macrophages in ischemic muscles, local chemokine overexpression was induced by designed chemokine-encoding DNA plasmids.

Results: We found that macrophages accumulate at perivascular positions along blood vessels in ischemic muscles from both humans and mice, where they express high levels of iNOS. Further, we demonstrated that the hyperemic response to heat was shifted from eNOS (endothelial)-dependence in healthy mouse muscles to completely rely on iNOS in ischemic muscle. Specific depletion of iNOS in macrophages did not affect vascular architecture but highly compromised the ability to upregulate blood flow in the ischemic muscle, which resulted in aggravated ischemic damage. The macrophages in ischemic muscles expressed high levels of CXCR4 and CCR2, and local overexpression of the corresponding chemokine CXCL12 but not CCL2 increased macrophage numbers and perivascular positioning in the ischemic muscle. As a result, CXCL12-overexpression increased the number of perfused blood vessels, improved functional muscle perfusion in an iNOS- and macrophage-dependent manner, and ultimately restored limb function.

Conclusions: This study establishes a new function for macrophages during tissue repair, as they regulate blood flow through the release of iNOS-produced NO. Further, we demonstrate that macrophages can be therapeutically targeted to improve blood flow regulation and functional recovery of ischemic tissues.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-395532OAI: oai:DiVA.org:uu-395532DiVA, id: diva2:1362484
Note

         * Indicates equal contribution

Available from: 2019-10-20 Created: 2019-10-20 Last updated: 2019-10-21
In thesis
1.
The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.

Open Access in DiVA

No full text in DiVA

By organisation
Department of Medical Cell BiologyDepartment of Immunology, Genetics and Pathology
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 4 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf