Natural products are used widely for preventing intimal hyperplasia (IH), a common cardiovascular disease. Four different cells initiate and progress IH, namely, vascular smooth muscle, adventitial and endothelial cells, and circulation or bone marrow-derived cells. Vascular smooth muscle cells (VSMCs) play a critical role in initiation and development of intimal thickening and formation of neointimal hyperplasia. In this review, we describe the different originating cells involved in vascular IH and emphasize the effect of different natural products on inhibiting abnormal cellular functions, such as VSMC proliferation and migration. We further present a classification for the different natural products like phenols, flavonoids, terpenes, and alkaloids that suppress VSMC growth. Abnormal VSMC physiology involves disturbance in MAPKs, PI3K/AKT, JAK-STAT, FAK, and NF-
Intimal hyperplasia (IH) is a fibroproliferative disorder observed in vascular pathogenesis particularly in vessel anastomotic stenosis, atherosclerosis, blockage of vessel grafts, angioplasty, and in-stent restenosis [
Many herbal medicines sourced from plants or foods have been used to prevent cardiovascular disease over the millennia. For example, green tea contains various flavanols that have antioxidative [
Graphic abstract for different natural compounds for inhibiting vascular smooth muscle cells proliferation and migration.
Recent clinical studies have shown that rapamycin A, an VSMC inhibitor, prevents development of IH-induced vascular endothelial dysfunction [
As stated earlier, four different cell types are involved in the initiation and progression of IH. These are VSMCs, vascular adventitial cells, VECs, and circulating bone marrow-derived cells (Figure
Four different cell origins contribute to blood vessel stenosis.
Endothelial-to-mesenchymal transition is a phenomenon where endothelial cells acquire a fibroproliferative mesenchymal phenotype through differential stimulation [
VSMCs in the normal vascular tunica media express a range of smooth muscle cell markers including smooth muscle cell myosin heavy chain (MYH11), 22-kDa SMC lineage-restricted protein (SM22
Most studies investigating inhibition of VSMCs adopt drugs like rapamycin, sirolimus, or tacrolimus to induce VSMC apoptosis and cell cycle arrest at G1/S phase, suppress ROS production, inhibit VSMC migration, and downregulate collagen deposition. These approaches do not recover the mature VSMC immunophenotypes, but they do decrease neointimal formation and prevent stenosis following vascular injury. To investigate the anticellular function of drugs on VSMCs many models have been established
Dietary supplements and traditional herbal medicines are complementary medication approaches used in every society and are widely used for preventing IH in Asia and in other developed countries [
The six signaling pathways involved in most drug inhibitory VSMC studies (Figure
Key genes and pathways involved in restraining cell cycle and movements of VSMCs with natural products.
Flavonoids are distributed throughout the plant kingdom and fulfill a diverse range of biological and pharmacological effects such as anti-inflammatory [
The structure, cells, category, source, and mechanism of typical flavonoid compounds on inhibiting VSMCs proliferation and migration.
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(2S)-naringenin |
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rASMCs | Flavonoid |
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G0/G1 ↓; cyclins D1 ↓; cyclins E ↓; CDK2/4 ↓; PCNA ↓; pho of rb protein ↓ |
Catechins |
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rASMCs and rat balloon injury | Flavonoid (Flavanols) | Green tea | TIMP-2 ↑, in vivo: TIMP-2 ↑ |
Icariin |
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hASMCs | Flavonoid (Prenylated flavonol glycoside) |
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pERK1/2 ↓; G1/S ↓; PCNA ↓ |
Morelloflavone |
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mVSMCs and mouse artery injury | Biflavonoid |
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FAK ↓; Src ↓; ERK ↓; RhoA ↓ |
Puerarin |
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rASMCs and rat balloon injury | Isoflavone |
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ROS ↓; Nox ↓; PKC;PKC |
Kaempferol |
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hpASMCs | Flavonoid | Widely (grapefruit, Ginkgo biloba) | miR-21 ↑; ROCK4/5/7 ↓ |
Nobiletin |
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rASMCs and rat balloon injury | Flavonoid | Widely (citrus fruits) | ROS ↓; pERK1/2 ↓; NF- |
Alpinetin |
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rASMCs | Flavonoid | Widely |
LDH ↓; NO ↓ |
Cyanidin-3-O-glucoside |
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mASMCs | Flavonoid |
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ROS ↓;NoxA1 ↓; pSTAT3 ↓ |
Hesperetin |
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rpASMCs | Flavonoid | Widely (lemons and sweet oranges) | Block G1/S; cyclin D1 ↓; cyclin E ↓; CDK2/4 ↓; p38 ↓; p27 ↑; regulate AKT/GSK3 |
Pinocembrin |
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rAMSCs and rat aortic rings injury | Flavonoid | Propolis | ERK1/2 ↓; MLC2 ↓; AT1R ↓ |
Glyceollins |
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hASMCs | Isoflavone | Soybean | Arrest G1/S phase; CDK2 ↓; cyclin D1 ↓; p27kip1 ↑; p53 ↑; ROS ↓; pPDGFr- |
Nobiletin is widely distributed in citrus fruits and has been reported to inhibit VSMC proliferation and migration
Polyphenols are distributed widely in vegetables and plants, green tea, black tea, and red wine. Recent studies have shown that they possess antioxidant, anti-inflammatory, and cardioprotective effects [
The structure, cells, category, source, and mechanism of typical polyphenols compounds on inhibiting VSMCs proliferation and migration.
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Salvianolic acid B |
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NeCs; HAECs and cholesterol-fed rabbits; |
Polyphenol |
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(1) p53 ↑; NeCs apoptosis, (2) ROS ↓; LDL oxidation ↓; lipid deposition ↓, (3) PCNA ↓; NQO1 ↓; via Nrf2-ARE-NQO1 pathway |
Caffeic acid phenethyl ester (CAPE) |
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rASMCs | Polyphenol |
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Blocking G0/1 to S phase; pp38 ↑;HiF1 |
Hispolon |
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rTA-A10-VSMCs | Polyphenol |
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MMP2 ↓;MMP9 ↓; TIMP-1 ↑;TIMP-2 ↑; pFAK ↓; pERK1/2 ↓;PI3K/AKT ↓ |
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rASMCs | Phenols |
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Inhibit DNA synthesis; activation of (Nrf2)/HO-1 pathway |
Resveratrol |
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ncTASMCs; |
Polyphenol | Widely |
c-Src ↓, Rac1 ↓, cdc42 ↓, IRS-1 ↓, MEKK1 ↓, |
Lithospermic acid |
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rTASMCs | Polyphenol |
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ROS ↓; pERK1/2 ↓; cyclin D1 ↓; arresting cell cycle progression at the G1 phase; MMP9 ↓ |
Magnolol |
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Cholesterol-fed rabbits; |
Polyphenol |
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(1) MCP-1 ↓, (2) Reduce collagen type I deposition; |
Obovatol |
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rASMCs; rats balloon injury | Biphenol |
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Blocks the cell cycle in G1 phase; CDKs ↓;p21cip1 ↓ |
Curcumin |
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rTASMCs; |
Phenols |
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(1) Inhibits PDGF Receptor Binding; PDGFr ↓; pERK1/2 ↓; pAkt ↓, (2) P-selectin ↓; E-selectin ↓; GPIIb/GPIIIa ↓, (3) MMP2 ↓; pRas ↓; MEK1/2 ↓; NF- |
Some studies have shown that curcumin (diarylheptanoid phenol) has potent antioxidant properties, which can be used for attenuating neointimal hyperplasia [
Curcumin shows the ideal biological effects of inhibiting abnormal VSMC proliferation and migration without compromising VEC proliferation or delaying reendothelialization after blood vessel injury. Curcumin inhibited platelet adhesion to brain microvascular endothelial cells by decreasing expression of P-selectin, E-selectin, and GPIIb/GPIIIa in a concentration-dependent manner (30-240
Terpenes are proven cell cycle inhibitors for various cell types, especially tumor cells [
The structure, cells, category, source, and mechanism of terpenes on inhibiting VSMCs abnormal proliferation, migration, and functions.
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Betulinic Acid |
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VSMCs | Terpene | Various plant sources widespread throughout the tropics | Inducing G1 Arrest and Apoptosis |
Parthenolide |
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rVSMCs | Sesquiterpene lactone |
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G0/G1 cell cycle arrest; p21 ↑; p27 ↑; I |
Plumericin |
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rAVSMCs | Iridoid (Terpene) |
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Block STAT3 signaling; arrest VSMCs in the G1/G0-phase; cyclin D1 ↓; pRb ↓ |
Paclitaxel |
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Rat balloon injury; hCASMCs (CC-2583) and VSMCs (CC-2571); rTASMCs and VECs | Diterpenoid |
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(1) prevent neointimal |
Epothilone D |
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rTASMCs; carotid artery injury | Diterpenoid |
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CDK2 ↓; pRb ↓ |
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hUVECs and VSMCs (A7r5); rat balloon injury | Terpene |
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Antioxidant; Casp 3/7/9 ↑; Migration ↓ |
Artemisinin |
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rVSMCs and rat balloon injury; rTASMCs | Sesquiterpene lactone |
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(1) arrest G0/G1 phase; cyclin D1/E ↓; CDK2/4 ↓; caspase 3/9 ↑; Bax ↑; Bcl-2 ↓, (2) PCNA ↓; caspase 3↑; Bax ↑; Bax/Bcl-2 ratio ↑ |
(S)-(-)-Perillic acid |
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rASMCs | Monoterpene | Widely | Protein prenylation ↓ |
Alkaloids are a group of naturally occurring chemical compounds that mostly contain basic nitrogen atoms. Alkaloids have diverse biological effects including those against tumors, hypertension, and pain. For vascular IH, some studies indicate that alkaloids hinder cell cycle progress, decrease ROS production, and inhibit VSMC migration (Table
The structure, cells, category, source, and mechanism of alkaloids on inhibiting VSMCs abnormal proliferation, migration, and functions.
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Piperine |
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rASMCs | Alkaloid |
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Selectively inhibit VSMCs |
Coptisine |
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rVSMCs | Alkaloid |
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Arrest G1/S phase |
Vinpocetine |
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rVSMCs and rat balloon injury; rASMCs and mice carotid artery ligation injury | Alkaloid vincamine | Lesser periwinkle plants | (1) ROS ↓; apoptosis ↓; pAkt ↓; pJNK1/2 ↓; I |
Halofuginone |
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bASMCs | Quinazolinone alkaloid |
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ECM synthesis and deposition ↓; Col I ↓ |
Murrayafoline A |
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rASMCs | Carbazole alkaloid |
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Arrest G1/S phase; cyclin D1/E ↓; CDK2/4 ↓; PCNA ↓; pRb ↓ |
As shown in Table
The structure, cells, category, source, and mechanism of promising compounds on suppressing VSMCs.
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Bilirubin |
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rVSMCs and mVSMCs; rat balloon injury | Ferric porphyrins | Heme | Inhibit MAPK signaling pathway; CDK2 ↓; Cyclin A/D1/E ↓; pRb ↓; YY1 ↓; p38 ↓ |
capsaicin |
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rASMCs | Capsaicinoids | Chili peppers | Inhibit DNA synthesis |
Emodin |
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hUVSMCs; rTASMCs; hASMCs; rat balloon injury | Anthraquinone |
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(1) Arrest cell cycle, induce apoptosis and autophagy; ROS ↑; p53 ↑, (2) PCNA ↓; c-myc ↓, (3) CRP ↓;ROS ↓; pERK1/2 ↓; p38 ↓; PPAR |
Rhein |
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hASMCs | Anthraquinone |
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Col I/III ↓; Wnt4/Dvl-1/ |
Ajoene |
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rASMCs | Organosulphur compound |
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Inhibit protein prenylation and cholesterol biosynthesis |
Gastrodin |
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rASMCs, mice artery injury | Glucoside |
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Block S-phase; stabilised p27Kip1; PCNA ↓; pERK1/2 ↓; pp38 ↓; pAkt ↓; pGSK3 |
Genipin |
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rTASMCs | Aglycon |
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HO-1 ↑; pERK/MAPK ↓; pAkt ↓; ROS ↓ |
Ginsenoside Rg1 |
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hASMCs; rat balloon injury | Steroid glycosides |
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(1) PCNA ↓; pERK2 ↓; c-fos ↓; MKP-1 ↑; (2) Arrest G1/S phase; GRKs ↓; PKC ↓; N-ras ↓; p21 ↑, (3) Cyclin D1 ↓; p53 ↑; p21WAF/CIP1 ↑; p27KIP1 ↑; inactivate PKB and ERK1/2 |
Ostruthin |
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rTASMCs | Coumarins |
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Inhibit DNA synthesis |
Lycopene |
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Rabbit artery injury | Carotenoid | Widely (tomatoes, red carrots,) | TG ↓; TC ↓; LDL-C ↓; HDL-C ↑; SOD ↑; T-AOC ↑; MDA ↓; PCNA ↓; pERK1/2 ↓; Nox1 ↓; |
Methyl Protodioscin |
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A7r5 VSMCs; rat balloon injury | Steroidal saponin |
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Arrest G1/S phase; ADAM15 ↓; MMP2/9 ↓; FAK ↓; ERK ↓; PI3K ↓; Akt ↓ |
Tanshinone IIA |
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rASMCs; rat balloon injury | Phenolic acids |
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Block cell cycle in G0/G1 phase; pERK1/2 ↓; c-fos ↓ |
Sulforaphane |
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rASMCs; rat balloon injury | Organosulfur compounds |
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p21 ↑; p53 ↑; CDK2 ↓; Cyclin E ↓; PCNA ↓ |
Methyl-protodioscin is a steroidal saponin that has been reported to inhibit neointimal formation by restraining VSMC proliferation and migration through downregulation of ADAM15, FAK, ERK, PI3K, Akt, and MMP-2/9 expression levels [
Most foods contain various biologically active constituents that act to prevent and cure neointimal hyperplasia by inhibiting abnormal VSMC proliferation and migration. A well-known carotenoid, lycopene, is abundant in tomatoes and its products and has been reported to inhibit neointimal hyperplasia in a rabbit restenosis model. It does this by regulation of blood lipid concentrations and suppression of oxidative stress [
Although many natural products inhibit VSMC function, most anti-smooth muscle proliferation drugs such as rapamycin (in-stent coating) also inhibit VEC proliferation and delay reendothelialization. This nonspecific cytotoxicity leads to restenosis and final graft or stent implantation failure. When screening for selective natural drugs that inhibit smooth muscle cell proliferation and migration, it is necessary to combine computer-aided design, bioinformatics, and a high-throughput screening platform. In this review, we selected certain drugs including chemosynthetic (idarubicin) and some natural (
The selected potential targets of the compounds.
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1 | MAPT | BCHE | MAOA | MAPT | MAPT | CHRM4 |
2 | MBNL1 | ACHE | MAOB | TDP1 | TLR9 | CHRM1 |
3 | MBNL2 | MAPK8 | SIGMAR1 | CXCR3 | TDP1 | CHRM2 |
4 | MBNL3 | MAPK9 | MBNL1 | SLC6A2 | Unknown | CHRM5 |
5 | MMP2 | MAPK10 | MBNL2 | SLC6A3 | MBNL1 | CHRM3 |
6 | MMP9 | MAPK11 | MBNL3 | LDLR | MBNL2 | BCHE |
7 | APP | MAPK14 | MAPT | VLDLR | MBNL3 | ADRA2A |
8 | SNCA | HTR1A | DRD2 | LRP8 | GLO1 | CYP2D6 |
9 | APLP2 | HTR1B | DRD3 | HSD11B1 | AKT1 | ADRA2B |
10 | SNCG | MAPT | HDAC3 | BACE1 | AKT2 | ADRA2C |
11 | SNCB | HTR2A | HDAC1 | HSD11B1L | AKT3 | ACHE |
12 | TDP1 | DRD2 | HDAC2 | BACE2 | HSD17B3 | HTR2A |
13 | EGFR | DRD1 | DYRK1A | HTR1A | HSD17B12 | HTR2C |
14 | ERBB2 | OPRM1 | HDAC6 | HTR1D | CRYZ | HTR2B |
15 | ERBB3 | OPRD1 | CTSL1 | HTR1B | APP | SIGMAR1 |
The compounds potential target: MAPT which is a common target.
This review highlighted the originating four cells that may contribute to IH and then focused on VSMCs due to their involvement in intima formation as a consequence of abnormal proliferation, migration, and physiology. It further summarized typical signaling pathways such as MAPKs, PI3K/Akt, JAK-STAT, FAK, and NF-
Intimal hyperplasia
Endothelial-to-mesenchymal transition
Rat aortic smooth muscle cells
Rat thoracic aortic smooth muscle cells
Vascular smooth muscle cells
Carotid artery
Rat aortic endothelial cells
Human aortic endothelial cells
Vascular endothelial cells
Human umbilical vein endothelial cells
Human umbilical vein smooth muscle cells
Neointimal cells
Rat thoracic aorta A10 vascular smooth muscle cells
Newborn calf thoracic aorta smooth muscle cells
Mice aortic smooth muscle cells
Human pulmonary artery smooth muscle cells
Rat pulmonary artery smooth muscle cells
Human coronary artery smooth muscle cells
Bovine aortic smooth muscle cells
Smooth muscle cell myosin heavy chain
SMC lineage-restricted protein
Alpha smooth muscle actin
Extracellular matrix
Tumor necrosis factor-
Platelet-derived growth factor
Extracellular signal-regulated kinase
Matrix metalloproteinase
Mitogen-activated protein kinase
c-Jun N terminal kinase
Proliferating cell nuclear antigen
Phosphatidylinositol-4,5-bisphosphate 3-kinase
Serine/threonine kinase 1
Cyclin-dependent kinase
Janus kinase
Signal transducer and activator of transcription protein
Focal adhesion kinase
Nuclear factor kappa B
Low-density lipoprotein
Reactive oxygen specie
Interleukin 1-
Lipopolysaccharide
NADPH oxidase
Tissue inhibitors of metalloproteinase
Nitric oxide synthase
Half maximal inhibitory concentration
MicroRNA-21
Nitric oxide
Lactate dehydrogenase
Nitric oxide synthase
Rho-associated protein kinase
Retinoblastoma tumor suppressor protein family.
The authors declare that they have no conflicts of interest.
Kang Xu, Mohanad Kh Al-ani, and Xin Pan designed the project, performed the experiments, collected the data, and wrote the manuscript. Qingjia Chi analyzed the data and wrote and revised the manuscript. Nianguo Dong and Xuefeng Qiu designed the project, gave financial support, and wrote and revised the manuscript. All authors read and approved the final manuscript.
This work was supported by National Key R&D Plan (2018YFA0108700, 2016YFA0101100), National Natural Science Foundation of China (81873471, 11602181, 30371414, 30571839, 30872540, 31330029, 81170214, 81270297, 11602181), the Fundamental Research Funds for the Central Universities, South-Central University for Nationalities (Grant Number: CZQ18019), the China Postdoctoral Science Foundation (Grant Number: 2018M630867), the Visiting Scholar Foundation of Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education (Grant Number: CQKLBST-2018-009 and CQKLBST-2018-006), and the Fundamental Research Funds for the Central Universities (WUT: 2016IVB063, 2018IB005). The authors thank Dr. Peng Zhu for help in organizing and writing the manuscript.