VEGFR1 signaling facilitates diabetic skin wound healing in mice

抄録

Aims: Signaling of vascular endothelial growth factor receptor 1 (VEGFR1) is suggested to involve in angiogenesis and lymphangiogenesis. The objective of the present study was to examine the role of VEGFR1 signaling in angiogenesis/lymphangiogenesis during diabetic skin wound healing.

Methods: VEGFR1-tyrosine kinase knockout mice (KO) or their wild counterparts (WT) were treated with streptozotosin (STZ) or vehicle (Veh). Full-thickness skin wounds were created on the backs of mice.

Results: Compared with non-diabetic mice (Veh/WT), wound healing and angiogenesis were suppressed in diabetic mice (STZ/WT) and non-diabetic KO mice (Veh/KO), with reduced expression of VEGF-A and CD31 in wound granulation tissues. Formation of lymphatic vessels was inhibited with reduced expression of VEGF-C, VEGF-D and VEGFR3. Accumulated VEGFR1-positive macrophages with VEGF-C or VEGF-D-expressing cells in granulation tissues were decreased. This was associated with attenuated expression of mannose receptor (MR) and transforming growth factor-beta (TGF β). Diabetic KO (STZ/KO) showed further delayed wound healing and wound-induced angiogenesis/lymphangiogenesis. Exaggerated reduction in recruitment of VEGFR1-positive macrophages and in expression of MR and TGF β was also demonstrated.

Conclusions: These results indicate that VEGFR1 signaling plays a role in angiogenesis/lymphangiogenesis through recruitment of VEGFR1-positive macrophages during diabetic wound healing.