Targeting PDGF/PDGFR Signaling Pathway by microRNA, lncRNA, and circRNA for Therapy of Vascular Diseases: A Narrow Review

Abstract

Despite the significant progress in diagnostic and therapeutic strategies, vascular diseases, such as cardiovascular diseases (CVDs) and respiratory diseases, still cannot be successfully eliminated. Vascular cells play a key role in maintaining vascular homeostasis. Notably, a variety of cells produce and secrete platelet-derived growth factors (PDGFs), which promote mitosis and induce the division, proliferation, and migration of vascular cells including vascular smooth muscle cells (SMCs), aortic SMCs, endothelial cells, and airway SMCs. Therefore, PDGF/PDGR receptor signaling pathways play vital roles in regulating the homeostasis of blood vessels and the onset and development of CVDs, such as atherosclerosis, and respiratory diseases including asthma and pulmonary arterial hypertension. Recently, accumulating evidence has demonstrated that microRNA, long-chain non-coding RNA, and circular RNA are involved in the regulation of PDGF/PDGFR signaling pathways through competitive interactions with target mRNAs, contributing to the occurrence and development of the above-mentioned diseases. These novel findings are useful for laboratory research and clinical studies. The aim of this article is to conclude the recent progresses in this field, particular the mechanisms of action of these non-coding RNAs in regulating vascular remodeling, providing potential strategies for the diagnosis, prevention, and treatment of vascular-dysfunction-related diseases, particularly CVDs and respiratory diseases.

Keywords: cardiovascular disease; non-coding RNA; platelet-derived growth factor; respiratory disease; vascular system.

Figure 1

PDGF dimers bind PDGFRα and PDGFRβ to activate distinct signaling pathways that are involved in the regulation of vascular cell proliferation, migration, and invasion. According to the available references, four different disulphide-linked dimers including PDGF-AA, PDGF-AB, PDGF-BB, and PDGF-CC are involved in regulating the phenotype switch of vascular cells, thereby regulating vessel homeostasis in different organs. ERK: extracellular signal-regulated kinase; JAK: Janus kinase; MMP: matrix metalloproteinase; Myc: myelocytomatosis oncogene gene; NF-κB: nuclear factor kappa-B; PDGF: platelet-derived growth factors; PDGFR: PDGF receptor; STAT: signal transducer and activator of transcription; VEGF: vascular endothelial growth factor; VSMC: vascular smooth muscle cells.

Figure 2

miRNAs target genes that are involved in the PDGF/PDGFR signaling pathways, modulating vascular cell phenotype switch and vascular diseases, such as atherosclerosis and Kawasaki disease. miRNAs are found to regulate various signaling pathways including CDK1/P21, IGF-1, KLF4, CyclinD1, PCNA, NF-κB p65, and MEKK1/ERK/KLF4 in different vascular cells. CDK1: cyclin-dependent kinase 1; ICAM-1: intercellular cell adhesion molecule-1; IGF: insulin-like growth factor; IGF-1R: IGR-1 receptor; KLF4: Krüppel-like factor 4; LDL: low-density lipoprotein; MEKK1: mitogen-activated protein kinase kinase 1; LOX-1: lectin-like oxidized LDL receptor-1; OX-LDL: oxidized low-density lipoprotein; PCNA: proliferating cell nuclear antigen; P21: kinase inhibitor cdkn1a; RelA: reticuloendotheliosis viral oncogene homolog A; SMCs: smooth muscle cells.

Figure 3

miRNAs target genes that are involved in the PDGF/PDGFR signaling pathways, modulating phenotype switch of PASMCs and airway SMCs, affecting the onset and development of pulmonary arterial hypertension and asthma. miRNAs regulate pulmonary hypertension via activating various molecules including C-Kit, P27Kip1, STAT3, TGF-β1/Smad2/3, PI3K/HDAC4, and NOR-1. miRNAs modulate asthma via targeting the signaling pathways, such as JAK2/STAT3, CyclinD1, NOR-1, and FGF1/MAPK/STAT1. C-Kit: mast/stem cell growth factor receptor kit; FGF1: fibroblast growth factor 1; JAK2: Janus kinase 2; Kip: kinase inhibition protein; MAPK: mitogen-activated protein kinase; NOR-1: neuron-derived orphan receptor 1; PASMC: primary pulmonary artery smooth muscle cell; Smad: drosophila mothers against decapentaplegic protein; STAT: signal transducer and activator of transcription; TGF-β1: transforming growth factor-β1.

Figure 4

lncRNAs regulate different pathways via sponging miRNAs to modulate cell proliferation and migration as well as inflammation, thereby affecting the occurrence and development of atherosclerosis, asthma, and liver fibrosis. AKT: protein kinase B; AMPK: AMP-activated protein kinase; ATG7: autophagy-related 7; PI3K: phosphatidylinositol 3-kinase; PTEN: phosphatase and tensin homolog deleted on chromosome ten.

Figure 5

Some circRNAs are found to sponge miRNAs to regulate molecules that are involved in the PDGF/PDGFR signaling pathways, controlling cell proliferation and migration, modulating the onset and development of atherosclerosis and asthma. FGF1: fibroblast growth factor 1; FRS2: fibroblast growth factor receptor substrate 2; HMGB1: high-mobility group box 1; IGF1: insulin-like growth factor 1; KCNA1: voltage-gated potassium channel subfamily A member 1; mTOR: mammalian target of rapamycin; TRAF6: tumor-necrosis-factor-receptor-associated factor 6; VAMP2: vesicle-associated membrane protein 2; VEGFA: vascular endothelial growth factor A.