The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease

Abstract

Mechanisms controlling vascular smooth muscle cell (VSMC) plasticity and renewal still remain to be elucidated completely. A class of small RNAs called microRNAs (miRs) regulate gene expression at the post-transcriptional level. Here, we show a critical role of the miR-143/145 cluster in SMC differentiation and vascular pathogenesis, also through the generation of a mouse model of miR-143 and -145 knockout (KO). We determined that the expression of miR-143 and -145 is decreased in acute and chronic vascular stress (transverse aortic constriction and in aortas of the ApoE KO mouse). In human aortic aneurysms, the expression of miR-143 and -145 was significantly decreased compared with control aortas. In addition, overexpression of miR-143 and -145 decreased neointimal formation in a rat model of acute vascular injury. An in-depth analysis of the miR-143/145 KO mouse model showed that this miR cluster is expressed mostly in the SMC compartment, both during development and postnatally, in vessels and SMC-containing organs. Loss of miR-143 and miR-145 expression induces structural modifications of the aorta, because of an incomplete differentiation of VSMCs. In conclusion, our results show that the miR-143/145 gene cluster has a critical role during SMC differentiation and strongly suggest its involvement in the reversion of the VSMC differentiation phenotype that occurs during vascular disease.

The miR-143/145 Cluster Is a Novel Transcriptional Target of Jagged-1/Notch Signaling in Vascular Smooth Muscle Cells

“…In addition, VSMC response to vascular injury is affected in null miR-143/ 145 mice (24,25), similar to loss of function phenotypes of Notch1 (26). In this report, we identify miR-143/145 as a novel, CBF1-dependent target of Jag-1/Notch signaling, and define its role in VSMC differentiation.…”

“…The miR-143/145 locus has been targeted in the mouse, and is not required for vascular development (23,24,35). However, altered vascular structure and morphology was reported in postnatal vessels, with pathological lesion formation (35) or abnormal response to vascular injury on the miR-143/145-null background (23).…”

Age‐related changes in miR‐143‐3p:Igfbp5 interactions affect muscle regeneration

“…In other tissues, miR‐143 impairs glucose metabolism through the induction of insulin resistance (Jordan et al ., 2011), regulates the contractility and maintenance of smooth muscle myoblasts (Elia et al ., 2009) and controls vascular remodelling following injury (Xin et al ., 2009) and intestinal epithelial regeneration (Chivukula et al ., 2014). …”

“…miR‐143‐3p (miR‐143) has an established role in the function of smooth muscle myoblasts and adipogenesis (Esau et al ., 2004; Cordes et al ., 2009; Elia et al ., 2009; Xin et al ., 2009). miR‐143‐5p is highly expressed in skeletal muscle tissue, and its expression is downregulated during aging (Kim et al ., 2014).…”

DiGeorge Syndrome Critical Region 8 (DGCR8) Protein-mediated microRNA Biogenesis Is Essential for Vascular Smooth Muscle Cell Development in Mice

“…miR-143/145 and miR-17/92 clusters were the most significantly down-regulated in the umbilical arteries of DGCR8 cKO embryos (supplemental Table 2). The miR-143/145 cluster modulates the VSMC phenotypic switch between proliferation and differentiation (21)(22)(23)(24). We found that in the umbilical arteries of DGCR8 cKO embryos, the expression of miR-143 and 145 decreased ϳ10-and 7-fold, respectively (supplemental Fig.…”