MicroRNA regulation of phenotypic transformations in vascular smooth muscle: relevance to vascular remodeling

Abstract

Alterations in the vascular smooth muscle cells (VSMC) phenotype play a critical role in the pathogenesis of several cardiovascular diseases, including hypertension, atherosclerosis, and restenosis after angioplasty. MicroRNAs (miRNAs) are a class of endogenous noncoding RNAs (approximately 19-25 nucleotides in length) that function as regulators in various physiological and pathophysiological events. Recent studies have suggested that aberrant miRNAs' expression might underlie VSMC phenotypic transformation, appearing to regulate the phenotypic transformations of VSMCs by targeting specific genes that either participate in the maintenance of the contractile phenotype or contribute to the transformation to alternate phenotypes, and affecting atherosclerosis, hypertension, and coronary artery disease by altering VSMC proliferation, migration, differentiation, inflammation, calcification, oxidative stress, and apoptosis, suggesting an important regulatory role in vascular remodeling for maintaining vascular homeostasis. This review outlines recent progress in the discovery of miRNAs and elucidation of their mechanisms of action and functions in VSMC phenotypic regulation. Importantly, as the literature supports roles for miRNAs in modulating vascular remodeling and for maintaining vascular homeostasis, this area of research will likely provide new insights into clinical diagnosis and prognosis and ultimately facilitate the identification of novel therapeutic targets.

Keywords: Contractile phenotype; Phenotypic transformation; Synthetic phenotype; VSMC; miRNA.

Fig. 1

MicroRNAs regulate synthetic phenotypic transformations in VSMC. Considerable amounts of miRNA, such as miR-221/222, miR-138, miR-24, and miR-146 through modulation of direct targets or in the presence of external stimuli can promote the conversion of VSMC to a synthetic phenotype. Growth factors, such as α-SMA, SM22α, and SMMHC, were significantly overexpressed during this process. The synthetic phenotype is characterized by increased proliferation and migration to maintain the stability of the VSMC synthetic phenotype against conversion to a contractile phenotype

Fig. 2

Merged enrichment map of target proteins of synthetic phenotype regulated by miRNAs obtained from KEGG and GO. A Linkages between target proteins associated with miRNA-influenced synthesis phenotypes were analyzed by R language; B histograms of three typical enrichment items for molecular function (red), cellular composition (blue), and biological processes (green), and the top 10 GO items in each category are plotted according to p value. C KEGG enrichment analysis network based on the association of target genes; the most significant one is marked in red

Fig. 3

MicroRNAs regulate contractile phenotype transformation in VSMC. Inhibition of VSMC proliferation and migration and acceleration of VSMC differentiation are direct evidence of promoted VSMC conversion to a contractile phenotype. Factors, such as miR-1, miR-145, miR-195, miR-124, miR-34c through modulation of direct targets, or external stimulating factors can slow cell proliferation and migration or maintain the contractile phenotype of VSMC by partially affecting apoptosis through miR-206. Moreover, miR-145 and miR-133 could directly improve the differentiation ability of VSMC. In this process, tropoelastin, osteopontin, thrombospondin, and other proteins characteristic of the VSMC contractile phenotype were highly expressed to prevent conversion to the synthetic phenotype

Fig. 4

Merged enrichment map of target proteins of contractile phenotype regulated by miRNAs obtained from KEGG and GO. A The linkage between miRNAs affecting contracted phenotype-associated target proteins was Analyzed by R language; B histograms of three typical enrichment items for molecular function (red), cellular composition (blue) and biological processes (green), and the top 10 GO items in each category were plotted according to p value. C KEGG enrichment analysis network based on the association of target genes, the most significant one is marked in red

Fig. 5

miRNAs regulate VSMC phenotypic transformations to influence vascular remodeling and homeostasis by regulating different pathophysiological aspects, thus affecting various cardiovascular disease processes. Vascular remodeling and homeostasis are key in many vascular diseases. miRNAs, as a class of small regulatory transcripts, can modulate the phenotypic transformation of VSMC to repair the balance between vascular function and injury by regulating the proliferation, migration and differentiation, oxidative stress and apoptosis, extracellular matrix (ECM) synthesis, inflammation, and osteoblast differentiation and calcification of VSMVs. Therefore, miRNAs have considerable potential for targeted therapy and prevention in cardiovascular diseases, including thoracic aortic coarctation, atherosclerosis, aortic aneurysm, diabetes, vasculitis, osteoporosis, and coronary artery disease

Fig. 6

miRNAs act on the calcification signaling pathway to regulate VSMC phenotypic transformation. Calcification is one of the key regulatory signals in VSMC phenotypic transformation. Activation of VSMC calcification was promoted by miR-324-3p via enhancement of PI3K3A and MAP2K1 or miR-762/714 via activation of NCKX4 and PMCA1 or miR-32 and miR-34b/c targeting RUNX2. Subsequently, Ca²⁺ can promote increased ERK1/2 expression through activation of RAS, which further regulates downstream key factors regulating cell proliferation, migration, and transcription. In addition, the key protein ERK1/2 can activate miR-31 or be regulated by miR-181b to affect VSMC performance transformation