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Correspondence to: Shuzhong Duan, MD, Department of Nephrology, Affiliated Hospital of Chengde Medical University, Chengde, Hebei Province, China. Tel.: 86-314-2270061; fax: 86+0314+2270061
Intimal hyperplasia (IH), a crucial histopathological injury, forms the basis of vascular stenosis and thrombogenesis. In addition, it is common in maladies such as stenosis at the anastomosis of arteriovenous fistula and restenosis after angioplasty. Various cellular and noncellular components play critical parts in the advancement of IH. This article reviews the distinctive components of IH, such as endothelial dysfunction, multiplication, and movement of vascular smooth muscle cells. Finally, in addition to synthesis of large amounts of extracellular matrix and inflammatory responses, which have frequently been studied in recent years, we offer a premise for clinical treatment with vascular smooth muscle cells.
Introduction
Adequate vascular access is a crucial lifeline for end-stage renal failure patients undergoing hemodialysis. One reason for the death of patients on hemodialysis is vascular access malfunction, which remains a difficult clinical problem to solve. The optimal type of vascular access for maintenance of patients undergoing hemodialysis is an Arteriovenous fistula (AVF). Nonmaturation occurs in 50% of AV fistulae and intimal hyperplasia (IH) is the leading cause of nonmaturation.
Excessive intimal hyperplasia in human coronary arteries before intimal lipid depositions is the initiation of coronary atherosclerosis and constitutes a therapeutic target.
A combination of upstream and downstream events is the typical feature that leads to dysfunction of the hemodialysis access (Fig. 1). Initial injury to the vessel wall, the most common upstream event, mainly includes vascular injury, surgical trauma, and hemodynamic changes. Generally arising from the organic reaction to upstream vascular harm, downstream events primarily incorporate increased vascular smooth muscle cell (VSMC) activities and the enhancement of IH.
Fig. 1(A) End-to-side anastomosis of arteriovenous fistula in patients undergoing haemodialysis. (B) The pathogenesis of vascular access malfunction can be divided into upstream and downstream events. Initial injury to the vessel wall is the most common upstream event and mainly includes vascular injury, surgical trauma, and hemodynamic changes. Downstream events involved biological responses to upstream vascular lesions and are mainly manifested as vascular smooth muscle cells changes and IH. Arrow represents the direction of blood flow.
IH appears to be a complex pathobiological process involving multicellular signaling and regeneration. Although the pathogenesis of IH has not been entirely elucidated, it is principally categorized into four essential stages: (1) Endothelial cells (ECs) injury; (2) inflammatory response; (3) phenotypic transdifferentiation, duplication, and movement of VSMCs; and (4) vessel lumen remodeling (involving incredibly persistent release of extracellular matrix [ECM] proteins) (Fig. 2). Thus far, few practical medications can effectively treat IH. However, the quest to identify components fundamental to the pathogenesis of IH will likely introduce new targets for clinical treatment.
Fig. 2Intimal hyperplasia can roughly be divided into the following processes: (1) endothelial dysfunction (especially related to shear forces caused by turbulence); (2) release of inflammatory cytokines; (3) phenotypic transformation, proliferation, and migration (and calcification) of VSMCs; (4) accumulation of extracellular matrix (ECM, synthesis over decomposition). NO, nitric oxide; eNOS, endothelial nitric oxide synthase; MMP, matrix metalloproteinase; VE-cadherin, vascular endothelial cadherin; VSMCs, vascular smooth muscle cells.
Blood streaming through the vasculature creates two fundamental mechanical forces: shear push, which is transmitted between ECs through intercellular junctions, and cyclic tensile force produced by longitudinal forces acting on cells amid the vascular movement. Shear stress, which can trigger biochemical signaling reactions in ECs, is the predominant force. ECs covering the internal surface of the vascular lumen are continually subjected to bloodstream grinding, which is interpreted as sheer stretch into biochemical signals that change cellular behavior.
The cell membranes of ECs contain numerous potential mechanoreceptors, such as integrins, receptor tyrosine kinases (RTKs), ion channels, heterotrimeric trimeric G proteins, G protein–coupled receptors (GPCRs), and supramolecular structures.
In addition, essential cilia, polysaccharide calyx, cell–cell intersections, and cytoskeletal components alter the lipid bilayer of ECs to contribute to versatile detection and/or transmission of biomechanical stimuli. Indeed, mechanoinduction can trigger a series of intracellular pathways to alter cell morphology and signaling. To control vascular physiology and remodeling, ECs have advanced complex mechanosensing capabilities to distinguish diverse features of the bloodstream, such as the rate and direction of blood flow.
The most well-studied mechanosensor is an EC-specific complex comprised of platelet EC adhesion molecule (PECAM-1) and vascular endothelial (VE)–cadherin. Recent studies found that the blood flow rate increases vascular pressure through an upstream pathway via PECAM-1, the binding of which switches to vimentin in the cytoskeleton. ECs transmit the force of the myocardium to PECAM-1 and subsequently activate endothelial nitric oxide synthase (eNOS) and phosphoinositide 3 kinase (PI3K), causing vasodilation.
Generally, low or oscillatory shear stretch signals enact these pathways and promote ECs injury, leading to IH. In contrast, heavy shear stretch within a certain extent is an inhibitory flag that enacts antithrombotic and anti-inflammatory proteins. Hence, sheer stretch is involved in directing endothelial homeostasis and, accordingly, the preparation of neointima formation.
Inflammation is a key factor of IH. After ECs injury, leukocytes enter into the vessel barrier as a result of chemotaxis. Subsequently, macrophages and neutrophils release proinflammatory cytokines and growth factors, which assist in the enrollment of white blood cells and direct VSMCs to initiate a phenotypic change, proliferate, and migrate to the site of injury, thus causing IH.
White blood cell enrollment is a complex multistage process driven by cytokines and chemokines secreted by VSMCs, which are themselves activated by ECs and leukocytes. These components, such as platelet-derived growth factor (PDGF) and transforming growth factor β (TGF-β), acts as inflammatory factors that cause harm to ECs and delicate tissue, and may advance IH.
Resolvin E1 normalizes contractility, Ca2+ sensitivity, and smooth muscle cell migration rate in TNFalpha- and IL-6-pretreated human pulmonary arteries.
Am J Physiol Lung Cell Mol Physiol.2015; 309: 776-788
Late evidence suggests that the inflammatory reaction is fundamentally enacted by activation of the nucleotide bound oligomeric domain-like receptor protein 3 (NLRP3) inflammasome in conjunction with interleukin (IL)-1β and caspase-1 activation. To disrupt the pathogenesis of IH, overexpression of Forkhead box P (FoxP) in ECs can essentially diminish NLRP3 inflammasome activation, white blood cell enlistment, and vascular barrier invasion.
During expansion of VSMCs, the nuclear factor-κB (NF-κB) acts as a fundamental controller of irritation. In mice, KCNQ1OT1 was confirmed to block the aggravation and expansion of VSMCs by inhibiting NF-κB expression, partially alleviating the intimal region and, thereby, IH.
Hereditary P300/CBP-associated factor (PCAF) has lysine acetyltransferase activity and advances NF-κB interceded aggravation, subsequently driving the advancement of IH after mediation. PCAF directs NF-κB-mediated inflammatory responses in two diverse ways. First, PCAF acetylates histones at the location of the NF-κB binding sites, making it easier for NF-κB to reach the deoxyribonucleic acid (DNA) at that location. Second, PCAF acetylates lysine accumulated within the p65 unit of NF-κB itself, expanding its ability to recognize DNA.
Proper ECs function is essential to maintaining vascular function because ECs control the adjustment of vasodilation and contract and anti-inflammation and proinflammation factors to preserve vascular tone. Profoundly dynamic nonstop monolayers of smooth ECs make up the endothelium, whereas ordinary ECs partition the vessel barrier from blood components while viably anticipating early changes in endothelial proliferation.
Under physiological conditions, ECs maintain well-regulated boundaries that are entirely and intensely controlled. Accordingly, disruption of ECs function plays a central role in human health and disease. When ECs function is disrupted, the introduction of subendothelial collagenous tissue can cause platelet attachment and accumulation, inflammatory cell invasion, thrombosis, and IH.
The breakdown of adherens junctions and modification of cytoskeletal components disrupt vascular function by advancing the retraction of ECs. Generally, ECs firmly associate between proximal luminal surfaces and their primary components associate with adherens junctions. VE-cadherin connects to p120-linked protein, β-linked protein, and platelet globule protein through its cytoplasmic auxiliary space to create adherences. The degradation of practical adherens junctions primary results from the dismantling of VE-cadherin (Fig. 3), suggesting that VE-cadherin plays a crucial part in maintaining selective vascular permeability to the numerous phosphatases that can affect endothelial barrier function. By directly or indirectly diminishing phosphorylation of proteins such as VE protein tyrosine phosphatase (VE-PTP) and protein tyrosine phosphatase (PTP)-μ, phosphatases such as sarcoma (Src) can promote VE-cadherin phosphorylation, leading to debilitated junctions.
A study focused on IH demonstrated that administration of 5-methoxytryptophan (5-MTP) to human umbilical vein-derived ECs can preserve tight junctions to protect ECs from lipopolysaccharide and cytokine-induced disruption by avoiding VE-cadherin and, accordingly, ECs.
In addition to VE-cadherin, Calcium (Ca2+) is a critical courier within the signaling pathway that influences ECs. Indeed, changes in intracellular Ca2+ concentrations trigger a signaling cascade that seriously influences EC function. Amid intense vascular damage, inflammatory mediators alter intracellular Ca2+ concentrations to increase activation of Ca2+-dependent proteins that advance ECs withdrawal and, hence, disrupt barrier function. For example, thrombin can act through GPCRs to drive an increase in intracellular Ca2+ and the ensuing activation of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ), myosin light chain kinase (MLCK), and membrane-linked protein A2. Together, these proteins advance the breakdown of extravascular endothelial adhesion proteins and the compression of actin, which disrupts barrier function.
In addition, certain members of the Krüppel-like translation figure (KLF) family of proteins have been recognized to modulate endothelial barrier function. Specifically, KLF2 ensures the accuracy of EC barrier function and blood vessel arrangement by promoting myosin light chain phosphorylation and increasing expression of the crucial junction protein occludin, which plays a non-negligible role
Fig. 3Dysfunction of endothelial cells involves VE-cadherin degradation and Ca2+ internal flow. Phosphatases, such as vascular endothelial protein tyrosine phosphatase and PTP-μ, can directly or indirectly reduce VE-cadherin phosphorylation. In contrast, focal adhesion kinase or Src can reduce VE-cadherin phosphorylation. Thrombin can combine with a GPCR to increase intracellular Ca2+, which subsequently activates Ca2+/CaMKIIδ, myosin light chain kinase, and membrane protein A2 to elicit changes in barrier function.
ECs not only provide a barrier between tissue and blood but also act as an endocrine organ. In addition to changes in cell morphology, ECs injury can arise in response to the release of endothelium-derived diastolic factors such as vasodilator prostaglandins, nitric oxide (NO), endothelium-dependent hyperpolarizing factors, and endothelium-derived contractile components, which play critical roles in controlling vascular tone and coagulation.
Among these factors, a vital mediator influencing vascular function and remodeling is endothelial-type NO, which exerts vasodilatory, anti-inflammatory, and vasoprotective effects. Endothelial-type NO is created by eNOS, which activates Ca2+-dependent and Ca2+-independent pathways. Calmodulin (CaM) activation is affected by phosphorylation of eNOS, which is regulated by estrogen and VE growth factor–initiated phosphorylation of Ser1177 through activation of the serine/threonine kinase Akt. Bradykinin-induced Ser1177 phosphorylation of eNOS is mediated by Ca2+/CaMKII,
(Fig. 4). NO release into the vascular lumen effectively inhibits platelet aggregation and vascular wall adhesion. In addition to preventing thrombosis, this blocks the release of PDGF, which prevents IH. Clofloxacin, an angiotensin type I receptor blocker, can restore NO production by increasing protein expression of guanosine triphosphate hydrolase and the content of tetrahydrobiopterin (BH4) in diabetic rats. In these rats, the selective aldosterone antidepressants, eplerenone and enalapril, decreased nicotinamide adenine dinucleotide phosphate oxidase activity and increased vascular BH4 levels, whereas angiotensin receptor inhibitors and statins reduced vascular oxidative stress and restored eNOS function.
VSMCs play essential roles in their various physiological forms. Through phenotypic changes, self-proliferation, movement, and various combinations of ECM proteins, VSMCs adopt different physiological
forms (sometimes excessively) during vascular injury and remodeling, such as stenosis at the anastomosis of AVF, restenosis after angioplasty, and repair after vessel barrier injury
In developing and ordinary vessels, VSMCs adopt a profoundly stable and contractile phenotype because of high expression levels of contractile marker proteins such as α-smooth muscle actin (α-SMA) and SM22α. Amid vascular stenosis, VSMCs can adopt a dedifferentiated and migrated phenotype by downregulating expression of vascular smooth muscle contractile markers and upregulating osteopontin protein expression
. In the context of vascular damage, activated inflammatory cells and VSMCs release growth factors, particularly PDGF, to drive the transition of VSMCs from a contractile to synthetic phenotype. PDGF-BB is considered one of the most potent stimulators of VSMCs expansion and movement. Moreover, PDGF-BB appears to promote the phenotypic alteration of VSMCs from contractile to synthetic cells, as indicated by increased osteopontin expression and diminished expression of contractile markers α-SMA and SM22α at the protein and gene levels. Pretreatment with Ca2+ antagonized the effect of PDGF-BB on VSMCs dedifferentiation in a dose-dependent manner. Binding factor carry, a serum response factor, can regulate the expression of synthetic marker genes of VSMCs in cooperation with the coactivator myocardin or coinhibitory factor Klf4, which may be a direct regulator of TGF-β, which unequivocally quells VSMCs differentiation. AP-1-mediated and NF-κB-mediated regulation of protein expression can modify VSMCs phenotypes, including downregulation of myocardial-related protein expression.
Cholesterol-induced expression of macrophage-associated markers in VSMCs occurs through miR-143/miR-145 during both myocardial and inflammatory signaling and is affected by KLF4. At present, Klf4 and phosphorylated Elk-1 are thought to play a crucial part in phenotypic switching of VSMCs.
In addition, it appears that relatively constitutive structural proteins, such as ECM proteins and heparin, can modify VSMCs phenotypes. Thus, combating IH can be accomplished by hindering phenotypic changes through the targets described above. For example, the rapamycin-binding domain of mTOR/P70S6K essentially restricts PDGF-BB-mediated phenotype changes, which in turn hinders VSMCs proliferation and migration.
VSMCs proliferation has enormous impacts on numerous growth factors (such as PDGF, insulin-like growth factor [IGF-1], epidermal growth factor, and fibroblast growth factor) and the downstream signaling resulting from their homologous kinase-active transmembrane cell surface receptors (i.e., RTKs). PDGF-BB homodimers are by far the foremost agonist of VSMCs proliferation. Upon binding to its receptor, PDGF can activate a series of protein kinase cascades and their mediated signaling pathways, such as the tyrosine-protein kinase, mitogen-activated protein kinase (MAPK), and phospholipid-dependent protein kinase pathways. PTPs neutralize the activation of RTKs by dephosphorylating their downstream signals. Notably, vasoactive substances angiotensin II (AngII) and thrombin, and the neurotransmitter 5-hydroxytryptamine, can increase VSMCs proliferation through GPCRs. In addition, integrins and ECM proteins promote VSMCs proliferation, as do cyclic nucleotide phosphodiesterases and telomerase length. However, tumor necrosis factor α, ILs, Ca2+ signaling, and receptive oxygen species can modify this control. The TGF family of proteins is dependent on environmental factors and thus inhibit the proliferation of VSMCs fundamentally. However, heparin, NO, and Wilms' tumor 1-conjugating protein hinder this control.
Previous studies demonstrate that Epithelial glycoprotein, a potent mitogen secreted by VSMCs, promotes the proliferation of VSMCs induced by AngII, endothelin-1, and thrombin. AngII induces cell proliferation mainly through the binding of angiotensin type I receptor. In addition, many studies have shown that IGF-1/insulin-related pathways can promote VSMCs proliferation. IGF-1 mediates the mitosis of VSMCs through the IGF-1 receptor (IGF1R) and PI3K. Furthermore, PI3K/Akt and extracellular-signal-regulated kinase 1/2 play essential roles in VSMCs proliferation. Notably, IGF1R plays a vital role in growth factor-induced VSMCs proliferation, as indicated by the inhibitory effect of antisense oligonucleotides targeting IGF1R. Moreover, growth factors trigger a variety of mitotic signaling pathways, whose patterns and responses are regulated by costimulatory signals provided by integrins.
VSMCs migration occurs during vascular development, repair, and remodeling. Numerous migration-promoting and antimigration molecules belonging to a wide range of chemical and functional families exist within the blood.
The migration of cells in vivo or in vitro commences from a series of coordinated modification events, many of which involve the transduction of external signals from cell surface receptors. Early signaling events trigger actin polymerization, giving rise to a driving edge of the cell that projects toward promotive chemotactic signals or along a path distinct from the thick extracellular framework. Unused central contact foci on the driving edge extend attachment of the cell layer to the framework, whereas a combination of actin movements in the cell provide contraction, cytoskeletal remodeling, and local contact peeling of the posterior edge, which pushes the cell toward stimulation. Migration factors activate signal transduction cascades to trigger cytoskeletal remodeling, alter cell adhesion to the ECM, and activate kinesins. To migrate, a VSMC must extend a platelet foot in the direction of stimulation through actin polymerization, detach the posterior edge by degrading the focal contact, and push itself forward through the force generated from myosin II.
Trimer G protein, Ca2+-dependent protein kinase, small G protein, and MAPK are key signal transduction elements. myosin light chain kinase and myosin II can be activated by any stimulation that increases the concentration of sarcoplasmic Ca2+. Whereas β1 integrins and FAK control VSMCs movement by mediating central attachment and actin cytoskeleton elements, myosin light chain phosphorylation controls cell withdrawal to promote movement. Thus, IH can be affected by altering β1 integrin expression, focal adhesion kinase phosphorylation, and myosin activation.
Under typical circumstances, VSMCs firmly wrap extracellular networks, which are not only a fundamental component supporting the vascular barrier but also a prerequisite for cell phenotypic direction and IH. With the assistance of an assortment of framework metalloproteinases (MMPs), VSMCs cross the versatile inward layer to the intima, rapidly proliferate, and release ECM proteins to thicken the intima of blood vessels.
Intemperate amassing of ECM in IH occurs because of two fundamental reasons: increased ECM formation and restricted ECM degradation, of which disrupted ECM degradation is more vital. MMPs are the predominant molecules involved in ECM degradation. Although their activity level is typically low under normal conditions, MMP activity increases amid repair or remodeling blood vessels. MMPs can be delivered as dissolvable or membrane-anchored proteases and have substrate-specific cleavage ECM components.
MMPs play a critical part in the advancement of IH due to their ability to degrade ECM. Notably, some network components can corrupt interactions with 25 MMPs and other proteinases. Among them, MMP-2 and MMP-9 have significant impacts on collagen and proteoglycan and can increase injury to the intima. Recent studies have reported that the expression of MMP-9 in the intima is associated with the migration of early proliferating cells to the intima to form new intima,
Proprotein convertase subtilisins/kexin 6 (PCSK6), a novel protease, may colocalize and interact with MMP2. Silencing of PCSK6 in human VSMCs in vitro led to increased MMP2 expression and decreased ECM degradation. In contrast, PCSK6 overexpression increased the proliferation and migration of VSMCs, subsequently advancing IH.
Within the pathological process of IH, MMPs secreted by VSMCs provide a pathway for cell migration through processing of ECM.
Prevention and Treatment
Research into the prevention and control of IH is also evolving with increased understanding of its underlying mechanisms, although this knowledge remains incomplete. At present, several prevention and control protocols exist for various aspects of IH: (1) Inhibition of proliferation and movement of VSMCs. Early evidence indicates that heparin decreases the region of IH, DNA and RNA amalgamation, and cell expansion and antagonizes platelet function to hinder VSCMs migration. However, achieving this effect requires a high-dose heparin bolster, which increases the chance of bleeding and limits its application, which is further complicated by failure to require oral heparin in advance.
Application of network MMP inhibitors can both hinder corruption of the ECM by MMPs and prevent the migration of mesangial VSMCs to ECs, but there are no clinically accessible drugs to realize this effect.
Total Panax notoginseng saponin inhibits vascular smooth muscle cell proliferation and migration and intimal hyperplasia by regulating WTAP/p16 signals via m6A modulation.
Gax transcript quality, and release of kinin can stabilize VSMCs in G0 or G1 stage. In addition, exposure to various antisense treatments, such as antisense proto-oncogene, antisense cell cycle controller quality, and mitomycin, can restrain VSMCs proliferation by controlling their expansion cycle. Moreover, antisense treatments for various cytokines (e.g., antisense PDGF and VEGF) and oncogenes (e.g., p53) can restrain VSMCs proliferation.
Indeed, the qualities of different targets can be changed in ECs and VSMCs by viral vectors (adenovirus, retrovirus poxvirus, adeno-associated infection, etc.) and nonviral vectors (cationic liposomal vectors and cationic multimeric vectors), thereby allowing direct or indicate conveyance strategies to hinder IH, that is, treatment of the target can be used to restrain IH by direct or indirect modification of ECs and VSMCs. However, the application of viral or genetic strategies to change the qualities of molecular targets in the clinic still requires a long period of exploration for safety.
Role of the endothelium in modulating neointimal formation: vasculoprotective approaches to attenuate restenosis after percutaneous coronary interventions.
can be used to restrain VSMCs proliferation. In addition, photodynamic treatment is a promising strategy to repress proliferation by invigorating the retained light sensitivity of pre-existing photosensitizers in tissues to release oxygen particles, which causes strong oxidation of cells that can be incorporated into laser ex vivo radiation treatment and intravascular laser radiation treatment.
The effect of the beta-D-xyloside naroparcil on circulating plasma glycosaminoglycans. An explanation for its known antithrombotic activity in the rabbit.
(2) Inhibitory inflammatory response (e.g., induced by omega-3 greasy acids) can also hinder the advancement of IH by restricting vascular inflammation.
(3) To diminish IH by hindering amalgamation and release of ECM proteins, we examined the composition, secretion, and presentation of ECM within the intima after vascular injury. The use of a specific Choke-counteracting agent and location B-peptide resistance to reduce accumulation of Choke, an imperative component of ECM, could decrease the amount of ECM within the intima and successfully limit IH.
Despite the fact that statins reduce blood lipid substances and play an advantageous role in promoting arterial opening, there are additional considerations such as the restriction of macrophage penetration and expansion/migration of VSMCs to smother the injury after arterialized IH; thus, inquiry in large animal models is necessary.
Surgical repair was traditionally the most effective treatment for AVF stenosis. However, the present standard of care for AVF stenosis is percutaneous transluminal angioplasty, which includes methods such as the placement of a stent-graft and balloon angioplasty.
(b) Common old balloon angioplasty: In plain old balloon angioplasty, its mechanism of action is powerful expansion of the lumen, causing deep rupture of the neointimal tissue. This rupture expands the cross-sectional area of the lumen and enhances blood flow.
DCBs force the drug on the surface of the balloon to come into contact briefly with the blood vessel wall via expansion. The antirestenosis drug is then released for treatment in the local area of the diseased blood vessel.
Paclitaxel, which is the active ingredient of the coating matrix, has a robust antiproliferative effect. Paclitaxel binds to the β-tubulin microtubule subunit and has a dose-dependent inhibition on the propagation and migration of arterial smooth muscle cells, and it acts against neointimal hyperplasia.
In addition, vascular intima damage caused by surgery should be avoided. An operation lacking in caution and recurring punctures can increase the damage to the vascular intima. Therefore, the operation should be slow and gentle. Vascular access measures are especially prone to vasospasm because of increased local processes of the vessels and an increase in sympathetic nervous system activity. This in turn leads to the impairment of blood flow. Therefore, care should be taken to avoid pinching.
Despite the present treatment methods and techniques that are constantly updated, a failure of dialysis treatment is still inevitable. Because of dissimilar types of stents and diverse lesion sites, the process of stent use can cause damage to the collateral circulation and affect the return of other major central veins, leading to the failure of dialysis treatment.
Balloon dilatation angioplasty can injure the intima, causing reactive hyperplasia of the intima, thereby also leading to the failure of dialysis treatment.
Paclitaxel coated balloon angioplasty vs. plain balloon angioplasty for haemodialysis arteriovenous access stenosis: a systematic review and a time to event meta-analysis of randomised controlled trials.
Several studies have shown the effectiveness of DCBs in prolonging lesion patency in patients with stenosis by vascular access. However, a few studies showed conflicting results in which the paclitaxel drug-eluting balloon angioplasty group failed to attain the desired efficacy end point, and the patency rate was similar to that with plain balloon angioplasty.
In addition, the response to DCBs application could be inconsistent because of different AVF stenosis sites. Therefore, further studies are required to examine the response at dissimilar stenosis sites. The use of drugs, such as paclitaxel as an antiproliferative agent, is controversial because studies have shown an increase in late mortality in cohorts of patients who receive drug-eluting therapy. No large randomized clinical trials have been performed to verify the conclusions of its clinical application.
Safety and efficacy of paclitaxel-eluting balloon angioplasty for dysfunctional hemodialysis access: a randomized trial comparing with angioplasty alone.
In summary, IH is closely related to EC injury, changes of VSMCs, hemodynamics, and inflammation, although the particular mechanism remains unclear. To generate in-depth understanding of the pathogenesis of IH, we must take advantage of innovations in genetics, cell biology, and imaging and combine basic thinking and clinical thinking with creature models and human models. Only then we will be able to establish a strong foundation for clinical diagnostics and treatment.
References
Cheung A.K.
Imrey P.B.
Alpers C.E.
et al.
Intimal hyperplasia, stenosis, and arteriovenous fistula maturation failure in the hemodialysis fistula maturation study.
Excessive intimal hyperplasia in human coronary arteries before intimal lipid depositions is the initiation of coronary atherosclerosis and constitutes a therapeutic target.
Resolvin E1 normalizes contractility, Ca2+ sensitivity, and smooth muscle cell migration rate in TNFalpha- and IL-6-pretreated human pulmonary arteries.
Am J Physiol Lung Cell Mol Physiol.2015; 309: 776-788
Total Panax notoginseng saponin inhibits vascular smooth muscle cell proliferation and migration and intimal hyperplasia by regulating WTAP/p16 signals via m6A modulation.
Role of the endothelium in modulating neointimal formation: vasculoprotective approaches to attenuate restenosis after percutaneous coronary interventions.
The effect of the beta-D-xyloside naroparcil on circulating plasma glycosaminoglycans. An explanation for its known antithrombotic activity in the rabbit.
Paclitaxel coated balloon angioplasty vs. plain balloon angioplasty for haemodialysis arteriovenous access stenosis: a systematic review and a time to event meta-analysis of randomised controlled trials.
Safety and efficacy of paclitaxel-eluting balloon angioplasty for dysfunctional hemodialysis access: a randomized trial comparing with angioplasty alone.
Author contributions: All authors participated in the design, interpretation of the studies, and review of the manuscript; M.S.J. performed the literature searching and wrote the manuscript; D.S.Z. designed, revised, and submitted the manuscript; L.Y. provided the second views during the manuscript preparation; W.H.H. searched for part of literature.
Disclosure: None.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Impact Statement: IH is the leading cause of arteriovenous fistula dysfunction. This article reviews the process of intimal hyperplasia, including endothelial cells injury; inflammatory response; phenotypic transdifferentiation, duplication, and movement of vascular smooth muscle cells; and vessel lumen remodeling which suggested new therapeutic targets for the treatment of arteriovenous fistula dysfunction.
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