The Role of Angiogenesis-Inducing microRNAs in Vascular Tissue Engineering

Impact statement Recent review articles have discussed the utilization of proangiogenic microRNAs (miRNAs) in angiogenesis and osteogenesis coupling and for bone tissue engineering applications. In this review, we discuss proangiogenic miRNAs that have been applied in vascular tissue engineering for different applications (i.e., not only for bone tissue engineering but also for peripheral arterial disease and stroke, cardiac diseases, and skin tissue engineering). This work provides an overview of the current state of utilization of proangiogenic miRNAs and emphasizes the importance of accuracy and dose of administration in designing future applications as these miRNAs can also be associated with the negative implications of cancer. Angiogenesis is an important process in tissue repair and regeneration as blood vessels are integral to supply nutrients to a functioning tissue. In this review, the application of microRNAs (miRNAs) or anti-miRNAs that can induce angiogenesis to aid in blood vessel formation for vascular tissue engineering in ischemic diseases such as peripheral arterial disease and stroke, cardiac diseases, and skin and bone tissue engineering is discussed. Endothelial cells (ECs) form the endothelium of the blood vessel and are recognized as the primary cell type that drives angiogenesis and studied in the applications that were reviewed. Besides ECs, mesenchymal stem cells can also play a pivotal role in these applications, specifically, by secreting growth factors or cytokines for paracrine signaling and/or as constituent cells in the new blood vessel formed. In addition to delivering miRNAs or cells transfected/transduced with miRNAs for angiogenesis and vascular tissue engineering, the utilization of extracellular vesicles (EVs), such as exosomes, microvesicles, and EVs collectively, has been more recently explored. Proangiogenic miRNAs and anti-miRNAs contribute to angiogenesis by targeting the 3 '-untranslated region of targets to upregulate proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and hypoxia-inducible factor-1 and increase the transduction of VEGF signaling through the PI3K/AKT and Ras/Raf/MEK/ERK signaling pathways such as phosphatase and tensin homolog or regulating the signaling of other pathways important for angiogenesis such as the Notch signaling pathway and the pathway to produce nitric oxide. In conclusion, angiogenesis-inducing miRNAs and anti-miRNAs are promising tools for vascular tissue engineering for several applications; however, future work should emphasize optimizing the delivery and usage of these therapies as miRNAs can also be associated with the negative implications of cancer.