Vascular Endothelial Growth Factor Receptor Type 1 Signaling Prevents Delayed Wound Healing in Diabetes by Attenuating the Production of IL-1β by Recruited Macrophages

Abstract

The persistence of proinflammatory macrophages, which are recruited to the granulation tissue, impairs the healing of diabetic wounds. Herein, we examined the role of vascular endothelial growth factor receptor type 1 (VEGFR1) signaling in streptozotocin (STZ)-induced diabetic wound healing. Angiogenesis, lymphangiogenesis, and the healing of full-thickness skin wounds were impaired in STZ-treated wild-type (WT) mice compared with vehicle-treated WT mice, with attenuated recruitment of VEGFR1-positive macrophages expressing vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D to the wound granulation tissue. These phenomena were even more prevalent in STZ-treated VEGFR1 tyrosine kinase knockout mice (VEGFR1 TK(-/-) mice). STZ-treated WT mice, but not STZ-treated VEGFR1 TK(-/-) mice, showed accelerated wound healing when treated with placenta growth factor. Compared with that of STZ-treated WT mice, the wound granulation tissue of STZ-treated VEGFR1 TK(-/-) mice contained more VEGFR1-positive cells expressing IL-1β [a classic (M1) activated macrophage marker] and fewer VEGFR1-positive cells expressing the mannose receptor [CD206; an alternatively activated (M2) macrophage marker]. Treatment of STZ-treated VEGFR1 TK(-/-) mice with an IL-1β-neutralizing antibody restored impaired wound healing and angiogenesis/lymphangiogenesis and induced macrophages in the wound granulation tissue to switch to an M2 phenotype. Taken together, these results suggest that VEGFR1 signaling plays a role in regulating the balance between macrophage phenotypes in STZ-induced diabetic wounds, prevents impaired diabetic wound healing, and promotes angiogenesis/lymphangiogenesis.

Interleukin-6 stimulates Akt and p38 MAPK phosphorylation and fibroblast migration in non-diabetic but not diabetic mice

“…Diabetic wounds, however, exhibit abnormal macrophage activation, showing insufficient M1 in the early stage and delayed activation of M2 [12, 13]. Macrophages are a major source of cytokines in wounds, and their dysfunction is known to be a factor in the pathogenesis of chronic wounds in diabetes [14–17]. Identifying the factors associated with macrophage dysfunction and cytokine dysregulation is therefore crucial for preventing wounds from becoming arrested at the inflammatory stage, as well as for promoting the healing of diabetic wounds [11, 18, 19].…”

Pathogenesis of wound healing disorders in the elderly

“…The infl ammasome -a protein complex located in the cytosol that activates proinfl ammatory protease enzymes and IL-1 β in human epidermal cells [ 27 ] -also plays a crucial role in wound physiology; its response to tissue damage deteriorates with age [ 28 ] . Remarkably, vascular endothelial growth factor receptor (VEGFR) type 1 signaling protects from disturbed wound healing in diabetes by inhibiting the production of IL-1 β by recruited macrophages, and regulating the equilibrium between different macrophage phenotypes [ 29 ] . In addition, members of the sirtuin protein family have been shown to contribute to the wound healing process in diabetic db/db mice through regulation of oxidative stress and angiogenesis [ 30 ] .…”

Effect of dual‐drug‐releasing micelle–hydrogel composite on wound healing in vivo in full‐thickness excision wound rat model

“…However, because of the release of pro‐inflammatory and cytotoxic mediators, uncontrolled activity of macrophages may become detrimental to tissue repair. Indeed, imbalanced inflammation characterized by increased numbers of macrophages is a hallmark of attenuated repair response in human diseases, including diabetes mellitus, vascular disease, and aging. Data presented in the current study (Fig.…”