|Year : 2019 | Volume
| Issue : 2 | Page : 22-26
Factors regulating the change of vascular smooth muscle cells in cardiovascular diseases: A mini review
Haocheng Li1, Qingfeng Sun1, Ye Yao2, Chao Yuan1, Gaoyan Liu1, Bao Jing1, Jingbo Li1, Haiyang Wang1
1 Department of Vascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
2 Department of Cardiac Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
|Date of Submission||24-Mar-2019|
|Date of Decision||23-May-2019|
|Date of Acceptance||17-Jun-2019|
|Date of Web Publication||27-Nov-2019|
Department of Vascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001
Source of Support: None, Conflict of Interest: None
Vascular smooth muscle cells (VSMCs) are responsible for blood vessel relaxation contraction and hemodynamics. Cardiovascular diseases (CVDs) are a major cause of human death worldwide, and the pathophysiological changes to the VSMCs such as apoptosis, hypertrophy, and migration contribute to these diseases. Herein, we recapitulated the importance of molecular factors relevant to the regulation of VSMCs and how VSMCs are involved in these pathophysiological changes. This is significant to the development of therapeutic treatments for various CVDs. A literature search was conducted to identify studies assessing the regulating factors of VSMCs using the Medline and PubMed databases from inception to February 1, 2019. Search terms were applied either as single or in combination. In the present review, we will discuss some of the influential factors that may affect and regulate the changes of VSMCs in CVDs.
Keywords: Cardiovascular diseases, molecules, noncoding RNAs, signaling pathways, vascular smooth muscle cells
|How to cite this article:|
Li H, Sun Q, Yao Y, Yuan C, Liu G, Jing B, Li J, Wang H. Factors regulating the change of vascular smooth muscle cells in cardiovascular diseases: A mini review. Transl Surg 2019;4:22-6
|How to cite this URL:|
Li H, Sun Q, Yao Y, Yuan C, Liu G, Jing B, Li J, Wang H. Factors regulating the change of vascular smooth muscle cells in cardiovascular diseases: A mini review. Transl Surg [serial online] 2019 [cited 2020 Feb 29];4:22-6. Available from: http://www.translsurg.com/text.asp?2019/4/2/22/271821
| Introduction|| |
Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. CVDs include coronary artery disease, aorticaneurysms, cerebrovascular disease, peripheral artery diseases, pulmonary arterial hypertension, and renal stenosis. The excessive growth of VSMCs involved in several type of CVDs such as atherosclerosis and restenosis. The loss of VSMC contractile functions leads to aortic aneurysms, and the phenotypic switching of VSMCs is associated with pulmonary arterial resistance and remodeling.
VSMCs are components of the blood vessel wall which can maintain blood pressure, vessel integrity, and function. Unlike skeletal muscle and myocardium. VSMCs exhibit high rates of proliferation, migration, and production of extracellular matrix (ECM) components such as collagen, elastin, and proteoglycans. VSMCs are of highly phenotype changes and highly plasticity. Understanding the molecular mechanisms of the pathophysiological changes of VSMCs is essential for the development of therapeutic treatments for various CVDs.
| Literature Search|| |
A literature search was conducted to identify studies assessing the regulating factors of VSMCs using the Medline and PubMed databases from inception to February 1, 2019. The following search terms were applied either as single or in combination: “VSMCs” OR “VSMCs” (Title/Abstract), AND “signal pathways” AND/OR “molecules,” AND/OR “noncoding RNAs” OR “MicroRNAs” OR “Long noncoding RNAs.” Abstracts were analyzed for relevance, and studies describing the regulating factors of VSMCs were retrieved.
| Signaling Pathways and Molecules Affecting Vascular Smooth Muscle Cell Functions|| |
Many signaling pathways and molecules can regulate the functions of VSMCs. The prominent molecule factors include platelet-derived growth factors and their receptors (PDGF and PDGFR); Src; epidermal growth factor (EGF); Angiotensin II (Ang-II) and endothelin I; and thrombin. The signaling pathways such as Ras/MAPK; JAK/STAT; phospholipase C-γ; Signaling pathways of insulin;PTEN/AKT; NOTCH and transforming growth factor β. We will briefly introduce the molecular and pathway functions of VSMCs and elucidate some of them.
PDGFs and their receptors are significant molecules which can regulate VSMC proliferation,, and among the PDFGs, PDGF-BB is the most potent stimulus. Past several decades have found that Src family can mediate the transcription of c-myc. Silencing Src can inhibit VSMC proliferation, and multiple signaling pathways in Ang-II induce VSMC proliferation. Fibroblast growth factors can promotethe VSMCs proliferation by influencing the Ras/MAPKand Src activated signaling pathways., In this part, we will elaborate on the molecule thrombin and reactive oxygen species (ROS).
Thrombin is a crucial molecule in homeostasis with procoagulant and anticoagulant activities., Thrombin can affect various cell types such as VSMCs, fibroblast, T lymphocyte, and monocytes., Studies have found a positive correlation between thrombin and VSMCs. The areas where thrombin bind to its receptor the expression of VSMCs also increased. The active PAR-1 which is induced by thrombin can enhance VSMC expression.,, Further, the study found that this positive regulation is functioned via NF-κB signaling pathway. Thrombin can also stimulate VSMCs proliferation via PI3K/AKT-1, ERK1/2, activating protein1 pathways.,
Reactive oxygen species
ROS include hydrogen peroxide, superoxide anion, and hydroxyl radical. All the species are the production of oxidative stress. ROS are oxygen-derived chemical molecules. these species can implicate in vascular cells dysfunction and DNA damage, lead to permanent cellular damage and death. The imbalance in the mitochondrial respiratory and oxidative enzymes results in excessive ROS. ROS can regulate fibroblast proliferation  and macrophage infiltration. In addition, they can regulate the degradation and remodeling of the ECM by upregulating the matrix metalloproteinases. The apoptosis of VSMCs induced by ROS may via activating NFκB and activator protein 1 signaling pathways.
Signaling pathways such as Ras/MAPK cascade are important in VSMC proliferation by inducing transcription of several genes which are linked to cell progression and proliferation. Phospholipase C-γ pathway can be activated by PDGFR-β. The activated pathway can suppress the mitogenic and chemotactic response to PDGF in VSMCs, thus inhibiting VSMC proliferation., Signal transducers and activators of transcription (STAT) is important in the regulation of cell cycle progression, which can be triggered by various factors, i.e., inflammatory cytokines and EGF., JAK can transduce extracellular signals via STAT pathway and affect VSMC migration and proliferation.
| Noncoding Rnas|| |
Noncoding RNAs which are range from 22 to 24 or >200 nt contribute to complexity regulatory networks. Recent studies have demonstrated that noncoding RNAs (including microRNAs [miRNAs] and long noncoding RNAs (lncRNAs]) are key players in the regulation of VSMC functions.,,
MicroRNAs are highly conserved noncoding RNAs that regulate gene expression at the posttranscriptional level by binding to complementary sequences in the 3' untranslated regions of target mRNA transcripts., They can inhibit or degrade the cleavage and translation of mRNA, exerting posttranscriptional effects and affecting the expression of genes and proteins.,, One microRNA can regulate various kinds of mRNAs, and one mRNA also can be regulated by a variety of miRs. This indicates that microRNAs participate in the pathological and physiological processes of cells in a complex way and play an extremely important regulatory role in cell growth, differentiation, proliferation, apoptosis, and metabolism. Studies have demonstrated that some miRNAs inhibit or promote VSMC proliferation., The following section describes the categories of miRNAs namely inhibition miRNAs and promotion miRNAs.
It was shown that miRNA-34a can significantly inhibit VSMC proliferation and migration, while VSMCs will be dramatically promoted proliferation if miRNA-34a is knocked down., miRNA-141 through targeting pregnancy-associated plasma protein A inhibits VSMC proliferation., It was shown that miRNA-206 can inhibit VSMC proliferation by silencing the expression of the gap junction protein connexin 43.
MicroRNA-17 overexpression in VSMCs by activating NF-κB P65 can promote VSMC proliferation. Furthermore, miRNA-675 promotes VSMC proliferation by targeting phosphatase and the tensin homolog (PTEN). miRNA-29a through downregulation of Fbw7/CDC4 enhances VSMC proliferation, and miRNA146a directly targets KLF4 can promote VSMCs proliferation.,
MicroRNA-21 promotes and inhibits vascular smooth muscle cell proliferation
On the one hand, studies suggest that miRNA-21 promotes VSMC proliferation and anti-apoptosis by silencing PTEN, a lipid and protein phosphatase and an important tumor suppressor protein, and activates the AKT to regulate the activity of a number of targets. On the other hand, some studies demonstrate that the miRNA-21 by silencing programmed cell death protein 4 (PDCD4) inhibits VSMC proliferation., Further studies need to be performed to understand the complicated role of miRNA-21.
Long noncoding RNAs
lncRNAs, classified as larger than 200 nucleotide-lncRNAs, lack distinct open reading frames., The expression of lncRNAs are lower than the protein-coding RNAs. lncRNAs involved in various biological, and have diverse biological functions such as host transcription of miRNAs  and molecule scaffolds for protein complexes; regulate genes expression. lncRNAs involved in VSMCs regulation whether the cells are normal or diseased.,. The overexpressed lncRNA H19 can inhibit VSMC proliferation and promote apoptosis via HIF1α. Another lncRNA, ANRIL, can also regulate VSMC proliferation and apoptosis., Studies have found that knockdown SERCA, a multi-exonic lncRNA, can downregulate the contractile function of VSMCs and upregulate VSMC migration.
| Conclusion|| |
VSMCs are components of the blood vessel wall, and their cell changes contribute to the etiology of many types of CVDs. As a result of extensive research, we have begun to understand their molecular functions and how these processes affect VSMCs. We clarify that the expression of noncoding RNA is related to human vascular diseases, which means that noncoding RNA may be mediating the occurrence and development of CVDs. The study of VSMC molecule is still in its early stage. Many questions such as to what extent these transcripts affect the function of VSMCs and whether they can be effective targets for the treatment of CVDs remain unanswered. Overall, although our research is still in its early stage, it represents a rapidly developing and novel research area. Future research will further clarify our understanding of VSMC biology and help us to use these interesting molecules for the treatment of CVDs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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