Circular RNA circPLOD2 regulates pericyte function by targeting the transcription factor KLF4

Circular RNAs (circRNAs) are generated by back-splicing and control cellular signaling and phenotypes. Pericytes stabilize the capillary structure and play an important role in the formation and maintenance of new blood vessels. Here, we characterized hypoxia-regulated circRNAs in human pericytes and showed that circPLOD2 is induced by hypoxia and regulates pericyte function. Silencing of circPLOD2 increased pericyte proliferation, endothelial-pericyte interaction and tube formation. Transcriptional profiling of circPLOD2-depleted cells and epigenomic analyses revealed widespread changes in gene expression and identified the circPLOD2-dependent regulation of the transcription factor KLF4 as a key effector of these changes. Importantly, overexpression of KLF4 was sufficient to reverse the effects on pericyte proliferation and endothelial-pericyte interactions observed after circPLOD2 depletion. Together, these data revealed a novel function of circPLOD2 in the control of pericyte proliferation and capillary formation and showed that circPLOD2-mediated regulation of KLF4 significantly contributes to the transcriptional response to hypoxia. HighlightsO_LIcircPLOD2 is upregulated in hypoxia in human vascular pericytes C_LIO_LISelective depletion of circPLOD2, but not linear PLOD2 mRNA, changes pericyte migration and endothelial-pericyte interaction C_LIO_LIcircPLOD2 depletion triggers widespread changes in gene expression that are mirrored in the transcriptional hypoxia response C_LIO_LIEpigenomic analyses pinpoint the transcription factor KLF4 as a central player in circPLOD2-mediated expression changes C_LIO_LIKLF4 overexpression is sufficient to rescue the changes in pericyte function caused by circPLOD2 depletion C_LI