VEGF-Induced Expression of miR-17–92 Cluster in Endothelial Cells Is Mediated by ERK/ELK1 Activation and Regulates Angiogenesis

Abstract

Supplemental Digital Content is available in the text.

MicroRNAs in endothelial cell homeostasis and vascular disease

“…Rapid changes in endothelial cell proliferation rates occurs following activation of endothelium by angiogenic cytokines [27–31,32,33 ■ ]. In fact, in the healthy adult, angiogenesis occurs only in select phases of the female reproductive cycle, to allow physiological adipose tissue expansion, as a protection mechanism in wound healing/tissue repair, and is almost exclusively associated with disorder when angiogenesis is induced by microenvironmental factors such as hypoxia or inflammation [34–39].…”

“…In the context of endothelial cells the miR-17–92 cluster is induced upon VEGF treatment [43]. In particular, extracellular-signal-regulated kinase/ETS transcription factor (Elk)1 activation is responsible for Elk-1-mediated transcription activation of the miR-17–92 cluster which in turn is necessary for endothelial cell proliferation and angiogenic sprouting [33 ■ ]. Interestingly, mice with conditional deletion of miR-17–92 have blunted physiological retinal angiogenesis during development and diminished VEGF-induced ear angiogenesis and tumor angiogenesis [33 ■ ].…”

“…In particular, extracellular-signal-regulated kinase/ETS transcription factor (Elk)1 activation is responsible for Elk-1-mediated transcription activation of the miR-17–92 cluster which in turn is necessary for endothelial cell proliferation and angiogenic sprouting [33 ■ ]. Interestingly, mice with conditional deletion of miR-17–92 have blunted physiological retinal angiogenesis during development and diminished VEGF-induced ear angiogenesis and tumor angiogenesis [33 ■ ]. The miR-106b-25 cluster, which is evolutionarily related to the miR-17–92 cluster, is also involved in angiogenesis, indeed its absence in a model of hindlimb ischemia impaired the capacity of restoring normal blood flow and significantly decreased capillary form[89], effect was attributed to the ability of the cluster to inhibit proliferation, migration, and viability in endothelial cells.…”

New Insights Into miR-17–92 Cluster Regulation and Angiogenesis

“…In this issue of Circulation Research, Chamorro-Jorganes et al 10 provide novel insight into the vascular endothelial growth factor (VEGF)-dependent transcriptional activation of the angiogenic miR-17-92 cluster. Both in vitro and in vivo state-of-the-art genetic approaches were used to delineate the transcriptional regulation of one of the key angiogenic miR clusters.…”

Pericyte-targeting drug delivery and tissue engineering

“…[46][47][48] Most antiangiogenic tumor therapy has been focused on preventing EC proliferation by targeting the vascular endothelial growth factor (VEGF) receptor. 49,50 PCs that communicate with ECs and unbalance the paracrine signaling between these cells may be a candidate for an alternative tumor cotarget. VEGF and PDGF, and their receptors, have been used as targets for tumor therapy.…”