Angiogenesis is a critical process in repair of tissue injury that is regulated by a delicate balance between pro‐ and antiangiogenic factors. In disease states associated with impaired angiogenesis, we identified that miR‐135a‐3p is rapidly induced and serves as an antiangiogenic microRNA (miRNA) by targeting endothelial cell (EC) p38 signaling in vitro and in vivo. MiR‐135a‐3p overexpression significantly inhibited EC proliferation, migration, and network tube formation in matrigel, whereas miR‐135‐3p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3′‐UTR reporter and miRNA ribonucleoprotein complex ‐immunoprecipitation assays, and small interfering RNA dependency studies revealed that miR‐135a‐3p inhibits the p38 signaling pathway in ECs by targeting huntingtin‐interacting protein 1 (HIP1). Local delivery of miR‐135a‐3p inhibitors to wounds of diabetic db/db mice markedly increased angiogenesis, granulation tissue thickness, and wound closure rates, whereas local delivery of miR‐135a‐3p mimics impaired these effects. Finally, through gain‐ and loss‐of‐function studies in human skin organoids as a model of tissue injury, we demonstrated that miR‐135a‐3p potently modulated p38 signaling and angiogenesis in response to VEGF stimulation by targeting HIP1. These findings establish miR‐135a‐3p as a pivotal regulator of pathophysiological angiogenesis and tissue repair by targeting a VEGF‐HIP1‐p38K signaling axis, providing new targets for angiogenic therapy to promote tissue repair.—Icli, B., Wu, W., Ozdemir, D., Li, H., Haemmig, S., Liu, X., Giatsidis, G., Cheng, H. S., Avci, S. N., Kurt, M., Lee, N., Guimaraes, R. B., Manica, A., Marchini, J. F., Rynning, S. E., Risnes, I., Hollan, I., Croce, K., Orgill, D. P., Feinberg, M. W. MicroRNA‐135a‐3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells. FASEB J. 33, 5599–5614 (2019). http://www.fasebj.org

Objective: In response to tissue injury, the appropriate progression of events in angiogenesis is controlled by a careful balance between pro-and anti-angiogenic factors. We aimed to identify and characterize microRNAs that regulate angiogenesis in response to tissue injury. Approach and Results: We show that in response to tissue injury, miR-615-5p is rapidly induced and serves as an anti-angiogenic miRNA by targeting endothelial cell (EC) VEGF-AKT/ eNOS signaling in vitro and in vivo. MiR-615-5p expression is increased in wounds of diabetic db/db mice, in plasma of human subjects with acute coronary syndromes, and in plasma and skin of human subjects with diabetes. Ectopic expression of miR-615-5p markedly inhibited EC proliferation, migration, network tube formation in matrigel, and the release of nitric oxide, whereas miR-615-5p neutralization had the opposite effects. Mechanistic studies using

Background and Objectives: Fluorescence from adrenal tumors can be detected with near-infrared imaging after injection with indocyanine green. However, it is unknown if adrenal tumors exhibit autofluorescence. The aim of this study was to determine whether adrenal tumors emit near-infrared autofluorescence (NIRAF).Methods: This was a prospective study of patients who underwent minimally invasive adrenalectomy at a tertiary center. Intraoperative images were analyzed to detect NIRAF with a 750 nm camera. Descriptive and comparative statistical analyses were performed.Results: Twenty-five adrenalectomies were examined. Only 11 tumors (44%), that originated from the cortex exhibited autofluorescence. A contrast distinction between the tumor and retroperitoneum was observed in 23 patients, whereas a contrast distinction between the tumor and normal adrenocortical tissue was seen in 12 patients. The overall fluorescence intensity of adrenal tumors was found to be variable and ranging between 0.3 and 5.6 times that of the background tissue.Pheochromocytoma, malignancy and adrenal cyst did not demonstrate NIRAF. Conclusion:This is the first study to show that adrenocortical tissue can demonstrate NIRAF. The pattern of fluorescence was similar to that observed after indocyanine green injection in our historical experience. NIRAF has a potential to be used as an intraoperative optical adjunct during adrenalectomy.