Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster

Abstract

VSMCs respond to changes in the local environment by adjusting their phenotype from contractile to synthetic, a phenomenon known as phenotypic modulation or switching. Failure of VSMCs to acquire and maintain the contractile phenotype plays a key role in a number of major human diseases, including arteriosclerosis. Although several regulatory circuits that control differentiation of SMCs have been identified, the decisive mechanisms that govern phenotypic modulation remain unknown. Here, we demonstrate that the mouse miR-143/145 cluster, expression of which is confined to SMCs during development, is required for VSMC acquisition of the contractile phenotype. VSMCs from miR-143/145-deficient mice were locked in the synthetic state, which incapacitated their contractile abilities and favored neointimal lesion development. Unbiased high-throughput, quantitative, mass spectrometry-based proteomics using reference mice labeled with stable isotopes allowed identification of miR-143/145 targets; these included angiotensin-converting enzyme (ACE), which might affect both the synthetic phenotype and contractile functions of VSMCs. Pharmacological inhibition of either ACE or the AT 1 receptor partially reversed vascular dysfunction and normalized gene expression in miR-143/145-deficient mice. We conclude that manipulation of miR-143/145 expression may offer a new approach for influencing vascular repair and attenuating arteriosclerotic pathogenesis.

Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants

“…Pharmacological inhibition of either ACE or the AT1 receptor partially reversed vascular dysfunction and normalized gene expression in miR-143/145-deficient mice. These results may offer a new approach to vascular repair and to the attenuation of arteriosclerotic pathogenesis (59).…”

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 role of blood flow and microRNAs in blood vessel development

“…To highlight the importance of miR-143 and miR-145 in VSMCs, Boettger and colleagues generated a mouse mutant for the microRNA cluster miR-143/145. Analysis of homozygous miR-143/145 mutant mice revealed a decrease in contractile VSMCs, an increase in proliferative precursors and formation of neointimal lesions (Boettger et al, 2009). Contractile behavior in other organs including, the gastrointestinal motility was not affected.…”

“…MiR-143 and miR-145 are abundantly expressed in VSMCs of arteries Ji et al, 2007), and the heart (Boettger et al, 2009;Cordes et al, 2009). During postnatal development the expression in heart is down regulated.…”

“…On the other hand miR-145/143 blocks the expression of Ets-like gene 1 (ELK-1) and Krüppel-like factor 4 (KLF4), transcription factors necessary for stimulating the SMC proliferation (Wang et al, 2008a;Yoshida et al, 2008). However, additional targets (KLF-4, KLF-5) and regulatory functions may exist (Boettger et al, 2009) (Nagai et al, 2005). Additional targets involved in VSMC phenotype switching, regulation of actin polymerization and cell migration were identified using TargetScan and PicTar prediction algorithms (Xin et al, 2009) but remain to be validated in vivo (Xin et al, 2009).…”