A1 Refereed original research article in a scientific journal
Perivascular Macrophages Regulate Blood Flow Following Tissue Damage
Authors: Vågesjö Evelina, Parv Kristel, Ahl David, Seignez Cédric, Hidalgo Carmen Herrera, Giraud Antoine, Leite Catarina, Korsgren Olle, Wallén Håkan, Juusola Greta, Hakovirta Harri H., Rundqvist Helene, Essand Magnus, Holm Lena, Johnson Randall S., Thålin Charlotte, Korpisalo Petra, Christoffersson Gustaf, Phillipson Mia
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Publication year: 2021
Journal: Circulation Research
Journal acronym: CIRC RES
Volume: 128
Issue: 11
First page : 1694
Last page: 1707
Number of pages: 14
ISSN: 0009-7330
eISSN: 1524-4571
DOI: https://doi.org/10.1161/CIRCRESAHA.120.318380
Web address : https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.120.318380
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.
