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Perivascular macrop...
Perivascular macrophages regulate blood flow following tissue damage
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- Vågesjö, Evelina (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Parv, Kristel (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Ahl, David (author)
- Uppsala universitet,Integrativ Fysiologi
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- Seignez, Cedric (author)
- Uppsala universitet,Integrativ Fysiologi
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- Herrera Hidalgo, Carmen (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Giraud, Antoine, 1972- (author)
- Uppsala universitet,Integrativ Fysiologi
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- Leite, Catarina (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Korsgren, Olle (author)
- Uppsala universitet,Klinisk immunologi
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- Wallen, H. (author)
- Karolinska Institutet
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- Juusola, G. (author)
- A.I.Virtanen Institute, University of Eastern Finland, Kuopio, Finland
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- Hakovirta, H. H. (author)
- Turku University Hospital, Department of Vascular Surgery, Turku, Finland
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- Rundqvist, H. (author)
- Karolinska Institutet
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- Essand, Magnus (author)
- Uppsala universitet,Klinisk immunologi
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- Holm, Lena (author)
- Uppsala universitet,Integrativ Fysiologi
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- Johnson, R.S. (author)
- Karolinska Institutet
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- Thålin, C. (author)
- Karolinska Institutet
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- Korpisalo, P. (author)
- Kuopio University Hospital, Heart Center, Kuopio, Finland
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- Christoffersson, Gustaf (author)
- Uppsala universitet,Integrativ Fysiologi
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- Phillipson, Mia, 1973- (author)
- Uppsala universitet,Integrativ Fysiologi
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(creator_code:org_t)
- Lippincott Williams & Wilkins, 2021
- 2021
- English.
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In: Circulation Research. - : Lippincott Williams & Wilkins. - 0009-7330 .- 1524-4571. ; 128:11, s. 1694-1707
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- Rationale: Ischemic injuries remain a leading cause of mortality and morbidity worldwide, and restoration of functional blood perfusion is vital to limit tissue damage and support healing.Objective: To reveal a novel role of macrophages in reestablishment of functional tissue perfusion following ischemic injury that can be targeted to improve tissue restoration.Methods and Results: Using intravital microscopy of ischemic hindlimb muscle in mice, and confocal microscopy of human tissues from amputated legs, we found that macrophages accumulated perivascularly in ischemic muscles, where they expressed high levels of iNOS (inducible nitric oxide [NO] synthase). Genetic depletion of iNOS specifically in macrophages (Cx3cr1-CreERT2;Nos2(fl/fl) or LysM-Cre;Nos2(fl/fl)) did not affect vascular architecture but highly compromised blood flow regulation in ischemic but not healthy muscle, which resulted in aggravated ischemic damage. Thus, the ability to upregulate blood flow was shifted from eNOS (endothelial)-dependence in healthy muscles to completely rely on macrophage-derived iNOS during ischemia. Macrophages in ischemic muscles expressed high levels of CXCR4 (C-X-C chemokine receptor type 4) and CCR2 (C-C chemokine receptor type 2), and local overexpression by DNA plasmids encoding the corresponding chemokines CXCL12 (stromal-derived factor 1) or CCL2 (chemokine [C-C motif] ligand 2) increased macrophage numbers, while CXCL12 but not CCL2 induced their perivascular positioning. As a result, CXCL12-overexpression increased the number of perfused blood vessels in the ischemic muscles, improved functional muscle perfusion in a macrophage-iNOS-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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Vågesjö, Evelina
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Parv, Kristel
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Ahl, David
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Seignez, Cedric
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Herrera Hidalgo, ...
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Giraud, Antoine, ...
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show more...
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Leite, Catarina
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Korsgren, Olle
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Wallen, H.
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Juusola, G.
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Hakovirta, H. H.
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Rundqvist, H.
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Essand, Magnus
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Holm, Lena
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Johnson, R.S.
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Thålin, C.
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Korpisalo, P.
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Christoffersson, ...
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Phillipson, Mia, ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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Circulation Rese ...
- By the university
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Uppsala University
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Karolinska Institutet