Arteriovenous fistulas (AVFs) are the preferred vascular access for hemodialysis of patients with end-stage renal disease. However, there is a high incidence of AVF failures caused by insufficient outward remodeling or venous neo-intimal hyperplasia formation. Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) play an important role in many cardiovascular diseases. Abnormal VSMC proliferation and migration could be abolished by inhibition of mitochondrial division.
Method
We found that abnormal proliferation and migration of VSMCs and increased mitochondrial fission were associated with AVF stenosis in patients. We also investigated the mechanisms, particularly the role of mitochondrial dynamics, underlying these VSMC behaviors. In vitro, we observed that inhibition of mitochondrial fission and Akt phosphorylation can diminish proliferation and migration of VSMCs induced by platelet-derived growth factor-BB (PDGF-BB). In vivo, daily intraperitoneal injections of mitochondrial division inhibitor 1 (Mdivi-1) decreased VSMC proliferation and reduced AVF wall thickness in a rat AVF model.
Conclusion and Result
Our results suggest that inhibition of mitochondrial fission improves AVF patency by reducing wall thickening through the PI3K/Akt signaling pathway. Therefore, inhibition of mitochondrial fission has the clinical potential to improve AVF patency.
Vascular Access WorkG. Clinical practice guidelines for vascular access. Am Journal Kidney Diseases: The Official Journal Natl Kidney Found2006; 48(Suppl 1): S248–S273.
2.
DemberLMBeckGJAllonM, et al.Effect of Clopidogrel on Early Failure of Arteriovenous Fistulas for Hemodialysis. JAMA2008; 299(18): 2164–2171.
3.
KarydisNBevisPBeckittT, et al.An implanted blood vessel support device for arteriovenous fistulas: a randomized controlled trial. Am J Kidney Dis2020; 75(1): 45–53.
ZonnebeldNHubertsWVan LoonMM, et al.Natural Vascular Remodelling After Arteriovenous Fistula Creation in Dialysis Patients With and Without Previous Ipsilateral Vascular Access. Eur J Vasc Endovascular Surg2020; 59(2): 277–287.
6.
JuncosJPTraczMJCroattAJ, et al.Genetic deficiency of heme oxygenase-1 impairs functionality and form of an arteriovenous fistula in the mouse. Kidney Int2008; 74(1): 47–51.
7.
JuncosJPGrandeJPKangL, et al.MCP-1 contributes to arteriovenous fistula failure. J Am Soc Nephrol2011; 22(1): 43–48.
8.
MarroneDPertosaGSimoneS, et al.Local activation of interleukin 6 signaling is associated with arteriovenous fistula stenosis in hemodialysis patients. Am J Kidney Dis2007; 49(5): 664–673.
9.
LiangKWYinSCTingCT, et al.Berberine inhibits platelet-derived growth factor-induced growth and migration partly through an AMPK-dependent pathway in vascular smooth muscle cells. Eur Journal Pharmacology2008; 590(1–3): 343–354.
10.
Roy-ChaudhuryPArendLZhangJ, et al.Neointimal hyperplasia in early arteriovenous fistula failure. Am J Kidney Dis2007; 50(5): 782–790.
11.
PengGXuJLiuR, et al.Isolation, culture and identification of pulmonary arterial smooth muscle cells from rat distal pulmonary arteries. Cytotechnology2017; 69(5): 831–840.
12.
SongSZhangMYiZ, et al.The role of PDGF-B/TGF-β1/neprilysin network in regulating endothelial-to-mesenchymal transition in pulmonary artery remodeling. Cell Signal2016; 28(10): 1489–1501.
13.
ChenYLiSGuoY, et al.Astaxanthin Attenuates Hypertensive Vascular Remodeling by Protecting Vascular Smooth Muscle Cells from Oxidative Stress-Induced Mitochondrial Dysfunction. Oxidative Medicine Cellular Longevity2020; 2020: 4629189.
14.
DasguptaAWuDTianL, et al.Mitochondria in the pulmonary vasculature in health and disease: oxygen‐sensing, metabolism, and dynamics. Compr Physiol2020; 10(2): 713–765.
15.
UmezuRKogaJIMatobaT, et al.Macrophage (Drp1) Dynamin-Related Protein 1 Accelerates Intimal Thickening After Vascular Injury. Arteriosclerosis, Thrombosis, Vascular Biology2020; 40(7): e214–e26.
16.
KuzmicicJDel CampoALópez-CrisostoC, et al.Mitochondrial Dynamics: a Potential New Therapeutic Target for Heart Failure. Revista Española de Cardiología (English Edition)2011; 64(10): 916–923.
17.
ParraVEisnerVChiongM, et al.Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis. Cardiovasc Res2008; 77(2): 387–397.
18.
ChenHChanDC. Emerging functions of mammalian mitochondrial fusion and fission. Hum Mol Genet2005; 142: R283–R289.
19.
CereghettiGMStangherlinAde BritoOM, et al.Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci2008; 105(41): 15803–15808.
20.
SongZGhochaniMMcCafferyJM, et al.Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion. Mol Biol Cel2009; 20(15): 3525–3532.
21.
RensenSSMDoevendansPAFMvan EysGJJM. Regulation and characteristics of vascular smooth muscle cell phenotypic diversity. Neth Heart J2007; 15(3): 100–108.
YangHHXuYXChenJY, et al.N-Butylidenephthalide Inhibits the Phenotypic Switch of VSMCs through Activation of AMPK and Prevents Stenosis in an Arteriovenous Fistula Rat Model. Int Journal Molecular Sciences2020; 21(19).
24.
CheungAKImreyPBAlpersCE, et al.Intimal Hyperplasia, Stenosis, and Arteriovenous Fistula Maturation Failure in the Hemodialysis Fistula Maturation Study. J Am Soc Nephrol2017; 28(10): 3005–3013.
25.
KongJWangFZhangJ, et al.Exosomes of Endothelial Progenitor Cells Inhibit Neointima Formation After Carotid Artery Injury. J Surg Res2018; 232: 398–407.
26.
WangCWenJZhouY, et al.Apelin induces vascular smooth muscle cells migration via a PI3K/Akt/FoxO3a/MMP-2 pathway. Int J Biochem Cel Biol2015; 69: 173–182.
27.
JiangXJiangLChengJ, et al.Inhibition of EZH2 by chidamide exerts antileukemia activity and increases chemosensitivity through Smo/Gli-1 pathway in acute myeloid leukemia. J Translational Med2021; 19(1): 117.
28.
NieQZhangJHeB, et al.A novel mechanism of protection against isoproterenol-induced cardiac inflammation via regulation of the SIRT1/NRF2 signaling pathway with a natural SIRT1 agonist. Eur J Pharmacol2020; 886: 173398.
29.
LivakKJSchmittgenTD. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method. Methods2001; 25(4): 402–408.
30.
HeXLianZYangY, et al.Long Non-coding RNA PEBP1P2 Suppresses Proliferative VSMCs Phenotypic Switching and Proliferation in Atherosclerosis. Mol Ther - Nucleic Acids2020; 22: 84–98.
31.
YangG-sZhengBQinY, et al.Salvia miltiorrhiza-derived miRNAs suppress vascular remodeling through regulating OTUD7B/KLF4/NMHC IIA axis. Theranostics2020; 10(17): 7787–7811.
32.
YuanXZhangTYaoF, et al.THO complex-dependent posttranscriptional control contributes to vascular smooth muscle cell fate decision. Circ Res2018; 123(5): 538–549.
33.
MahmoudADBallantyneMDMiscianinovV, et al.The human-specific and smooth muscle cell-enriched LncRNA SMILR promotes proliferation by regulating mitotic CENPF mRNA and drives cell-cycle progression which can be targeted to limit vascular remodeling. Circ Res2019; 125(5): 535–551.
34.
LuQ-BWanM-YWangP-Y, et al.Chicoric acid prevents PDGF-BB-induced VSMC dedifferentiation, proliferation and migration by suppressing ROS/NFκB/mTOR/P70S6K signaling cascade. Redox Biol2018; 14: 656–668.
35.
BoytardLHadiTSilvestroM, et al.Lung-derived HMGB1 is detrimental for vascular remodeling of metabolically imbalanced arterial macrophages. Nat Commun2020; 11(1): 4311.
36.
KyyriäinenJEkolle Ndode-EkaneXPitkänenA. Dynamics of PDGFRβ expression in different cell types after brain injury. Glia2017; 65(2): 322–341.
37.
WangHYinY-GHuangH, et al.Transplantation of EPCs overexpressing PDGFR-β promotes vascular repair in the early phase after vascular injury. BMC Cardiovasc Disord2016; 16(1): 179.
38.
WangHYinYLiW, et al.Over-Expression of PDGFR-β Promotes PDGF-Induced Proliferation, Migration, and Angiogenesis of EPCs through PI3K/Akt Signaling Pathway. PLoS One2012; 7(2): e30503.
39.
DuqueJCVazquez-PadronRI. Myofibroblasts: the ideal target to prevent arteriovenous fistula failure?Kidney Int2014; 85(2): 234–236.
40.
XuTDongQLuoY, et al.Porphyromonas gingivalis infection promotes mitochondrial dysfunction through Drp1-dependent mitochondrial fission in endothelial cells. Int J Oral Sci2021; 13(1): 28.
41.
FuPEpshteinYRamchandranR, et al.Essential role for paxillin tyrosine phosphorylation in LPS-induced mitochondrial fission, ROS generation and lung endothelial barrier loss. Scientific Rep2021; 11(1): 17546.
42.
XieJCuiYChenX, et al.VDAC1 regulates mitophagy in NLRP3 inflammasome activation in retinal capillary endothelial cells under high-glucose conditions. Exp Eye Res2021; 209: 108640.
43.
GaoQYZhangHFTaoJ, et al.Mitochondrial fission and mitophagy reciprocally orchestrate cardiac fibroblasts activation. Front Cell Developmental Biology2020; 8: 629397.
44.
WangYLuMXiongL, et al.Drp1-mediated mitochondrial fission promotes renal fibroblast activation and fibrogenesis. Cel Death Dis2020; 11(1): 29.
45.
CampbellCA. The Enhanced Productivity Program. J Am Diet Assoc1985; 85(11): 1479–1482.
46.
MathewOPRangannaKMathewJ, et al.Cellular effects of butyrate on vascular smooth muscle cells are mediated through disparate actions on dual targets, histone deacetylase (HDAC) Activity and PI3K/Akt signaling network. Int Journal Molecular Sciences2019; 20(12).
47.
ZhangQCaoYLuoQ, et al.The transient receptor potential vanilloid-3 regulates hypoxia-mediated pulmonary artery smooth muscle cells proliferation via PI3K/AKT signaling pathway. Cel Prolif2018; 51(3): e12436.
