Targeting macrophages for enhanced vascular integrity and healing in ischemic injuries

Uppsala UniversityJun 6 2024

Innate immune cells including macrophages and neutrophils have unique properties that allows them to quickly accumulate in large numbers at the site of infection or injury. A new study from researchers at Uppsala University establishes that macrophage in the adult ischemic muscle induce a phenotype switch into mural cells to support restoration of functional blood flow and thereby promote healing. This finding pinpoints macrophages as a potential target for therapeutically enhancing vascular integrity and healing of ischemic injuries.

Manifestations of cardiovascular diseases are caused by impaired tissue perfusion, and subsequent injury and loss of tissue function. Rapid re-establishment of functional blood flow is critical following an ischemic event to limit the extent and severity of tissue damage, as well as allowing for healing and regaining function. A hallmark of ischemic injury is rapid accumulation of immune cells including macrophages at the affected site, which is crucial for tissue regeneration and remodeling.

In injured muscle, including human infarcted myocardium, macrophages were recently described to localize to perivascular positions where they become more elongated and embrace the newly formed vasculature. This cellular morphology resembles that of mural cells, which are crucial for maintaining blood flow by reducing vascular leakage and promoting vessel maturation, but whether macrophages in injured muscle take on mural cell functions to improve healing have not been explored.

The current study, published in Nature Cardiovascular Research, demonstrates that perivascular macrophages in the ischemic muscle upregulated several proteins that are associated with mural cells while downregulating those associated with immune cell functions. Single-cell RNA-sequencing of fate-mapped macrophages from ischemic mouse muscles identified a subpopulation of macrophages that shifted their transcriptome from expression of macrophage markers to mural cell markers such as PDGFRβ. This macrophage switch was proven functionally relevant, as induction of macrophage-specific PDGFRβ-deficiency prevented their perivascular macrophage phenotype, impaired vessel maturation and increased vessel leakiness, which ultimately reduced limb function. Thus, macrophages in injured tissues not only develop a mural cell-like morphology and transcriptome but also adopt mural cell functions that are important for healing ischemic injuries.

In conclusion, macrophages in adult ischemic tissue were demonstrated to undergo a cellular program to morphologically, transcriptomically and functionally resemble mural cells while weakening their macrophage identity. The macrophage-to-mural cell-like phenotypic switch is crucial for restoring tissue function and demonstrate that innate immune cells in adult tissue can serve as a cellular resource and take over functions of other cell types to promote tissue repair. This novel finding warrants further exploration as a potential target for immunotherapies to enhance healing.