A BMP4-angiomiR connection in angiogenesis.

117: 734-749. Angiogenesis, the formation of new vessels, is regulated by the migration, proliferation and structural re-organisation of the endothelium. It is important in development and tissue homeostasis, while angiogenesis also contributes to the pathogenesis of cancer and ocular disorders (1). Several factors have been implicated in the control of angiogenic signalling. For instance, bone morphogenic proteins (BMPs), which trigger multiple transcriptional changes through the SMAD signal transduction pathway, have been shown to exert proangiogenic actions; however the underlying molecular mechanisms remain elusive (2). In this issue of the journal, the article by Esser et al. links, for the first time, the proangiogenic effects of BMPs with the regulation of microRNAs (3). The latter are short non-coding RNA sequences that inhibit expression of target genes through complementary binding to their mRNA transcripts and induction of mRNA degradation; miRNAs have been implicated in multiple disorders, including vascular pathologies (4). Esser et al. identified in their work two miRNAs, miR-126–5p and miR-494, to be upand downregulated, respectively, in BMP4-treated endothelial cells (3). Overexpression and inhibition studies in endothelial cells demonstrated that miR-126–5p is pro-angiogenic, while miR-494 acts in an anti-angiogenic fashion, as assessed by several functional experiments in vitro and in vivo. The authors furthermore show that the proangiogenic function of miR-126–5p is mediated through targeting of the anti-angiogenic molecule thrombospondin-1, thus extending findings that miR-126–5p promotes endothelial proliferation by suppressing DLK-1 (5). On the other hand, the anti-angiogenic actions of miR-494 are achieved through interference with BMPER translation and indirect reduction of basic fibroblast growth factor levels. Thus, BMP4 promotes pro-angiogenic endothelial cell functions by enhancing expression of miR-126–5p and down-regulating anti-angiogenic miR-494 (3). The work by Esser et al not only identifies the differential angiogenesis-regulatory functions of miR-126–5p and miR-494, thereby underlining the importance of microRNA regulation for endothelial function, but also links BMP4-induced angiogenesis with these two miRNAs. Importantly, these insights may contribute to the development of novel treatment methods for diseases related to pathological angiogenesis.