Abstract
Meteorin-like (Metrnl) is a novel secreted protein with various biological activities. In this study, we investigated whether and how Metrnl regulated skin wound healing in mice. Global Metrnl gene knockout mice (Metrnl−/−) and endothelial cell-specific Metrnl gene knockout mice (EC-Metrnl−/−) were generated. Eight-mm-diameter full-thickness excisional wound was made on the dorsum of each mouse. The skin wounds were photographed and analyzed. In C57BL/6 mice, we observed that Metrnl expression levels were markedly increased in skin wound tissues. We found that both global and endothelial cell-specific Metrnl gene knockout significantly retarded mouse skin wound healing, and endothelial Metrnl was the key factor affecting wound healing and angiogenesis. The proliferation, migration and tube formation ability of primary human umbilical vein endothelial cells (HUVECs) were inhibited by Metrnl knockdown, but significantly promoted by addition of recombinant Metrnl (10 ng/mL). Metrnl knockdown abolished the proliferation of endothelial cells stimulated by recombinant VEGFA (10 ng/mL) but not by recombinant bFGF (10 ng/mL). We further revealed that Metrnl deficiency impaired VEGFA downstream AKT/eNOS activation in vitro and in vivo. The damaged angiogenetic activity in Metrnl knockdown HUVECs was partly rescued by addition of AKT activator SC79 (10 μM). In conclusion, Metrnl deficiency retards skin wound healing in mice, which is related to impaired endothelial Metrnl-mediated angiogenesis. Metrnl deficiency impairs angiogenesis by inhibiting AKT/eNOS signaling pathway.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China Major Project (82030110 and 81730098 to CYM), Medical Innovation Major Project (16CXZ009 to CYM), and Naval Medical University Project (2018-CGPZ-A03 to CYM).
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CYM and TYX designed the study. TYX, SLQ, JXZ, JS, ZWM, JXL, FYY, SLZ, HYZ and SNW performed the experiments. CYM, TYX, SLQ, JXZ, JS, SLZ and ZYL analyzed the data. CYM, TYX, SLQ and JXZ wrote and revised the manuscript.
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Xu, Ty., Qing, Sl., Zhao, Jx. et al. Metrnl deficiency retards skin wound healing in mice by inhibiting AKT/eNOS signaling and angiogenesis. Acta Pharmacol Sin 44, 1790–1800 (2023). https://doi.org/10.1038/s41401-023-01090-x
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DOI: https://doi.org/10.1038/s41401-023-01090-x