MicroRNA26 attenuates vascular smooth muscle maturation via endothelial BMP signalling

Abstract

As small regulatory transcripts, microRNAs (miRs) act as genetic ‘fine tuners’ of posttranscriptional events, and as genetic switches to promote phenotypic switching. The miR miR26a targets the BMP signalling effector, smad1 . We show that loss of miR26a leads to hemorrhage (a loss of vascular stability) in vivo , suggesting altered vascular differentiation. Reduction in miR26a levels increases smad1 mRNA and phospho-Smad1 (pSmad1) levels. We show that increasing BMP signalling by overexpression of smad1 also leads to hemorrhage. Normalization of Smad1 levels through double knockdown of miR26a and smad1 rescues hemorrhage, suggesting a direct relationship between miR26a , smad1 and vascular stability. Using an in vivo BMP genetic reporter and pSmad1 staining, we show that the effect of miR26a on smooth muscle differentiation is non-autonomous; BMP signalling is active in embryonic endothelial cells, but not in smooth muscle cells. Nonetheless, increased BMP signalling due to loss of miR26a results in an increase in acta2 -expressing smooth muscle cell numbers and promotes a differentiated smooth muscle morphology. Similarly, forced expression of smad1 in endothelial cells leads to an increase in smooth muscle cell number and coverage. Furthermore, smooth muscle phenotypes caused by inhibition of the BMP pathway are rescued by loss of miR26a . Taken together, our data suggest that miR26a modulates BMP signalling in endothelial cells and indirectly promotes a differentiated smooth muscle phenotype. Our data highlights how crosstalk from BMP-responsive endothelium to smooth muscle is important for smooth muscle differentiation.

The origin and mechanisms of smooth muscle cell development in vertebrates

“…Another miRNA, miR26a, has been proposed to regulate mural cell differentiation and function, both in zebrafish and in mice (Leeper et al, 2011). Although the mechanism and the cell-autonomous function of this miRNA is still controversial, miR-26a acts at the intersection between PDGF and the BMP/TGFβ family during vSMC maturation (Watterston et al, 2019;Yang et al, 2017).…”

The biology of bone morphogenetic protein signaling pathway in cerebrovascular system

“…In addition to endothelial cells, smooth muscle proliferation, differentiation, and migration are also the crucial steps in neovascularization. Researches showed that BMP signaling plays an important role in angiogenesis by regulating smooth muscle cell function [ 32 , 33 ]. Vascular proliferative disorders are characterized by the proliferation of vascular smooth muscle cells and excessive extracellular matrix synthesis.…”

Non-Coding RNAs and Hereditary Hemorrhagic Telangiectasia

“…However, numerous miRs have been identified to be regulated by and target components of the TGFβ pathway in a variety of tissues and disease conditions [ 85 ]. MiR-26 has recently been shown to be involved in vascular stability, where its knockdown in zebrafish led to vascular hemorrhage [ 96 ]. MiR-26 from ECs can regulate vascular smooth muscle cell (VSMC) differentiation in a paracrine manner [ 96 ].…”

“…MiR-26 has recently been shown to be involved in vascular stability, where its knockdown in zebrafish led to vascular hemorrhage [ 96 ]. MiR-26 from ECs can regulate vascular smooth muscle cell (VSMC) differentiation in a paracrine manner [ 96 ]. It was shown that a decrease in miR-26 leads to an increase in its target, SMAD1, resulting in VSMC dysregulation and hemorrhage [ 96 ].…”

“…MiR-26 from ECs can regulate vascular smooth muscle cell (VSMC) differentiation in a paracrine manner [ 96 ]. It was shown that a decrease in miR-26 leads to an increase in its target, SMAD1, resulting in VSMC dysregulation and hemorrhage [ 96 ]. Another study demonstrated that the overexpression of miR-148b can improve migration, proliferation and angiogenesis in HUVECs by targeting SMAD2 and TGFβRII [ 97 ].…”