Dual Role of MiR-21-Mediated Signaling in HUVECs and Rat Surgical Flap under Normoxia and Hypoxia Condition

Restoring sufficient vascularity of the ischemia/hypoxia flap is always the critical issue in flap surgeries. In a previous studies microRNA-21 (miR-21) expression was upregulated after rat skin flap surgery. MiR-21 has been reported to be induced by hypoxia and the function of miR-21 involves in the process of angiogenesis. However, the precise regulatory mechanisms in miR-21-mediated pathways are still unclear. These issues were investigated via in vitro and in vivo experiments in this study. In human umbilical vein endothelial cells (HUVEC), the expression of hsa-miR-21-5p was induced after hypoxic culture and the induction of hsa-miR-21-5p was suppressed after sequential normoxic culture. Moreover, transfection of hsa-miR-21-5p mimic enhanced tube formation capacity in normoxia, but attenuated it in hypoxia. Furthermore, bioinformatic analysis suggested that SMAD7 was a predicted target of hsa-miR-21-5p. Our results demonstrated the effect of hsa-miR-21-5p was different on SMAD7 expression in normoxia and hypoxia. In rat skin flaps, blockage of miR-21-5p significantly increased angiogenesis via analysis of color laser Doppler imaging and repressed SMAD7 expression in ischemic skin tissue. Our study showed the opposite effect of miR-21-5p mediating angiogenesis in normoxia and hypoxia, providing important implications regarding the design of novel miRNA-based therapeutic strategies in flap surgeries.