FMRP regulates endothelial cell proliferation and angiogenesis via the miR-181a-CaM-CaMKII pathway.

Abstract

RNA binding proteins (RBPs) and microRNAs have emerged as crucial post-transcriptional regulators of gene expression. Although the role of Fragile X mental retardation protein (FMRP) has been well studied in the brain, the function of FMRP in endothelial cells remains unknown. In our study, we showed that FMRP controlled human umbilical vein endothelial cells (HUVECs) proliferation and angiogenesis via the miR-181a-mediated calmodulin (CaM)/CaMKII pathway. The knockdown of FMRP induced miR-181a expression and contributed to endothelial cell proliferation and angiogenesis. Furthermore, we identified CaM as a downstream target of miR-181a in endothelial cells. Additionally, tumor necrosis factor-ɑ (TNF-ɑ) treatment specifically decreased the activity of the CaM/CaMKII pathway through the dephosphorylation of FMRP and upregulation of miR-181a. Finally, the overexpression of constitutively phosphorylated FMRP rescued the TNF-ɑ-impaired endothelial cell proliferation and angiogenesis by activating the CaM/CaMKII pathway and downregulating miR-181a, which suggested there was a pivotal role of FMRP in vascular integrity in response to inflammatory stimuli. Thus, our study supports a novel function and mechanism involving FMRP and the miR-181a-CaM-CaMKII pathway may be a therapeutic target for protecting against inflammation-induced vascular diseases.