The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review

Muhamad Taufik Ismail; Dyah Wulan Anggrahini; Sofia Mubarika Haryana; Budi Yuli Setianto

doi:10.12688/f1000research.147482.2

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Systematic Review

Revised

The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review

[version 2; peer review: 1 approved]

Muhamad Taufik Ismail ¹, Dyah Wulan Anggrahini¹, Sofia Mubarika Haryana², Budi Yuli Setianto¹

PUBLISHED 14 Nov 2024

Author details Author details

¹ Cardiology and Vascular Medicine, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, Special Region of Yogyakarta, 55281, Indonesia
² Histology and Cell Biology, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, Special Region of Yogyakarta, 55281, Indonesia

Muhamad Taufik Ismail
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing

Dyah Wulan Anggrahini
Roles: Data Curation, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing

Sofia Mubarika Haryana
Roles: Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing

Budi Yuli Setianto
Roles: Methodology, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background

Chronic limb-threatening ischemia (CLTI) is the most advanced stage of peripheral artery disease (PAD) and has poor clinical outcomes. Recently, stimulating arteriogenesis has been proposed to improve clinical outcomes. Several studies have shown that miRNAs have beneficial effects on limb ischemia related to arteriogenesis. This study aimed to review the roles of therapeutic miRNAs in the arteriogenesis of limb ischemia.

Methods

A systematic search was conducted through July 2021 using the PubMed, Scopus, and ScienceDirect databases. Two authors independently assessed studies that investigated the role of miRNAs in the arteriogenesis of limb ischemia, both in vivo and in clinical studies.

Results

All selected studies were in vivo studies, with a total of 36 articles and 28 types of miRNAs. miRNAs potentially regulate arteriogenesis by targeting different targets. The following miRNAs were upregulated to enhance arteriogenesis: miRNA-126-3p, -93, -675, -143-3p, -130a, -210, -146b, -21, -let-7g, -132/212, -150, and 155. Meanwhile, microRNAs needed to be downregulated, namely: miRNA-939-5p, -503, -199a-5p, -146a, -92a, -14q32 microRNA gene cluster, -15a/16, -100, -133a, -139-5p, -223, -352, -615-5p, -15b/5p, -124-3p, and 29a. MiRNA-126 was the most studied miRNA, and SPRED1 was the most common target of microRNA. However, the included studies showed high heterogeneity in terms of inducing hindlimb ischemia, the timing of administration, and the method used for evaluating arteriogenesis. Moreover, most studies presented unclear or high-risk bias.

Conclusion

MicroRNA application in a preclinical model of hindlimb ischemia has beneficial effects on arteriogenesis. This result indicates that miRNAs might be potentially beneficial in patients with CLTI.

Registration

The review protocol was registered with PROSPERO under registration number CRD42024484988.

Keywords

Keywords: microRNA, arteriogenesis, limb ischemia, gene target

Corresponding author: Muhamad Taufik Ismail

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2024 Ismail MT et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Ismail MT, Anggrahini DW, Haryana SM and Setianto BY. The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review [version 2; peer review: 1 approved]. F1000Research 2024, 13:470 (https://doi.org/10.12688/f1000research.147482.2) First published: 09 May 2024, 13:470 (https://doi.org/10.12688/f1000research.147482.1) Latest published: 14 Nov 2024, 13:470 (https://doi.org/10.12688/f1000research.147482.2)

Revised Amendments from Version 1

We revised a sentence from introduction that explains the role of miRNA in the angiogenic signalling pathway to prevent potential misunderstanding. The original sentence was written in a way that suggested miRNA could signal independently, whereas in fact, miRNA requires interaction with proteins to exert its effect.
We also added method used to reduce risk of interobserver bias, improved resolution of the figure, and made a minor revision to clarify that curcumin does not contain miRNA but rather upregulates miRNA expression.

See the authors' detailed response to the review by Brian H Annex

Introduction

Chronic limb-threatening ischemia (CLTI) is a severe form of peripheral artery disease (PAD) due to the blockage of blood vessels.¹ Its amputation and mortality rates using a conservative approach are still high at 27% and 18% at 12 months after diagnosis, respectively,² despite being successfully revascularized.³^,⁴ Patients who present with late-onset and severe degree of tissue damage have the highest risk of amputation.⁴ Therefore, other therapeutic approaches need to be developed.

Genetic or cellular-based therapeutic approaches have been developed to increase neovascularization in the form of arteriogenesis and angiogenesis.¹ Unfortunately, angiogenesis is inadequate for replacing occluded or stenotic arteries. Furthermore, the long distance between the stenotic vessel and tissue hypoperfusion makes it more relevant to arteriogenesis than angiogenesis.⁵ Therefore, patients with CLTI generally require more arteriogenesis than angiogenesis.⁶

Studies on stem cell therapy for CLTI in clinical studies recently has not yet shown promising outcome.¹ It is possibly due to inability of stem cells in the ischemic condition.⁶ Similar result occurred with the trials of growth factors administration in CLTI patients.⁷ The expectation of increase neovascularization to compensate the ischemic limb, comes into a failure due to angiogenic signaling resistance. Therefore, miRNAs may offer a solution by alleviating impaired angiogenic signaling pathways and overcoming angiogenic resistance.⁸

Several miRNAs can improve arteriogenesis through different signaling pathways, either by increasing or inhibiting their expression depending on a specific type of miRNA.⁸ Arteriogenesis consists of two phases: an early inflammatory phase followed by an increase in blood vessel diameter, remodeling, and vessel maturation. Furthermore, several processes including proliferation of endothelial cells, smooth muscle cells, and remodeling of tunica adventitia are also essential for arteriogenesis.⁹ MicroRNAs can interfere those processes through gene regulation, since several genes are needed, particularly involved in the proliferation of endothelial cells, smooth muscle cells, activation of adhesion molecules, regulation of extracellular matrix, and regulation of growth factors and their receptors.¹⁰ Therefore, this study was aimed to review the role of therapeutic microRNAs in arteriogenesis process of limb ischemia.

Methods

The review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) database (registration number: CRD42024484988), however the protocol has yet to be published. We performed this systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

Search strategy

We searched for basic and clinical studies published in the PubMed, Scopus, and ScienceDirect databases on July 25, 2021. The literature is limited to English. We use the PICO strategy to answer this research question. The following terms were used for the literature search: (peripheral arterial disease OR peripheral artery disease OR chronic limb threatening Ischemia OR critical limb ischemia OR hindlimb Ischemia OR hind-limb ischemia OR femoral artery ligation OR hindlimb) AND (microRNA OR microRNAs OR miRNAs OR “micro RNA” OR miRNA OR “micro RNAs”) AND (angiogenesis OR arteriogenesis OR neovascularization OR collateral).

Eligibility criteria

Two authors (MT and DA) independently assessed the eligibility of the studies. The inclusion criteria were as follows: 1) Explaining the role of miRNAs in the arteriogenesis process of limb ischemia, either in vivo or clinical studies; 2) if in vivo study, inducing limb ischemia in animal models must be clearly described; 3) articles published in full-text journals; 4) Articles in English; and 5) articles assessing arteriogenesis using imaging or staining methods. The exclusion criteria were as follows: 1) the study involved only an in vitro study, 2) there was no control group in an in vivo study, and 3) the study was not conducted as primary research.

Data extraction

Two authors independently extracted the data from the included studies (MT and DA). The extracted data included the author’s name, publication year, animal models (type of animal, strain, age, how to induce limb ischemia, concomitant conditions, and if any animal gender was also included), type of microRNA, administration method in intervention and control groups, and techniques for evaluating arteriogenesis, including time points of assessment and outcomes. Any disagreements between the authors were resolved through discussion with senior reviewers (BY and SM) to reach a consensus. Owing to the high heterogeneity of the included studies, a meta-analysis could not be conducted. We developed ‘Characteristics of study’ tables to summarize and compare the data above.

Risk of bias assessment

The risk of bias was evaluated by two authors (MT and DA) using the SYRCLE’s risk of bias tool for animal studies. Disagreements were resolved through discussion.

Results

Search results

A systematic search of several databases identified 1317 relevant papers for this study (PRISMA Flowchart for The Systematic Review).⁵⁹ A total of 130 articles remained after removing duplicate publications and screening titles and abstracts. Furthermore, 3 articles with no full text available and 91 studies were not included because there was no analysis of miRNA in arteriogenesis. Therefore, 36 articles with 28 types of miRNAs were eligible for further analysis in this systematic review. The selected articles showed substantial heterogeneity, including animal models, intervention approaches, control groups, timing of administration, and methodology used to assess arteriogenesis.

Study characteristics

All the selected studies in Characteristics of Study ( Table 1)⁵⁹ show that strain, animal models, concomitant conditions, and techniques used to induce limb ischemia varied among studies. Almost all of the studies (n=35, 97,2%) used a rodent as a model, of which 33 studies used mice and 2 studies used rats. BALB/c and C57Bl/6 were the most commonly used mouse strains. The two strains used in this study were Fischer and Adult Sprague-Dawley rats. Furthermore, only one study used New Zealand White rabbits. Regarding concomitant conditions, diabetic mice were used in five studies and immunocompromised mice were used in two studies, 2 studies used hypercholesterolemic mice model, and 1 study used aging mice. Three studies used genetically modified mice compared to wild-type mice to determine the effect of a specific type of microRNA on arteriogenesis. Moreover, the techniques used to create hindlimb ischemia vary widely varied.⁵⁹

Table 1. MicroRNAs involved in arteriogenesis.

MiRNA	Expression (Therapeutic Purpose)	Details	Target
let-7g	↑	• let-7g enhanced expression of VEGF-A and VEGFR-2 through targeting HIF-3α and TP53. Moreover, let-7g influenced the splicing factor SC35, which consequently increased the alternative splicing of VEGF-A, from VEGF-A_165b (anti-angiogenic isoform) to VEGF-A_164a (pro-angiogenic isoform).¹¹	HIF-3α and TP53.
15a/16	↓	• Inhibition of miR-15a/16 enhanced arteriogenesis and angiogenesis in a mouse model of limb ischemia.¹² • Overexpression of miR-15a or-16 decreased Tie2 at the protein level.¹³	• VEGF-A and AKT3 • Tie2
14q32 microRNA gene cluster	↓	• Inhibition of miR-329, miR-487b, miR-494, and miR-495 led to arteriogenesis and angiogenesis.¹⁰	-
15b/5p	↓	• Regulating arteriogenesis and angiogenesis via targeting AKT3/eNOS pathway.¹⁴	AKT3
21	↑	• Human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) contained miR-21 which repaired neovascularization by increasing the activity of HIF-1α by targeting CHIP.¹⁵	CHIP
29a	↓	• Downregulation of MiR29a and upregulation of ADAM12 in ischemia with hyperglycemia state was impaired. Knocking down miR29a was adequate for fixing ADAM12 upregulation in ischemia with a hyperglycemia state. Hence, improving perfusion and angiogenesis even when vascular endothelial growth factor signaling was impaired.¹⁶	ADAM12
92a	↓	• Inhibition of miR-92a contributed to enhancing angiogenesis and arteriogenesis.¹⁷	mRNA encoding integrin subunit alpha5
93	↑	• miR-93 impeded interferon regulatory factor-9 to reduce the production of IRG1–itaconic acid, therefore it stimulated M2-like polarization in ischemic muscle. Consequently, it increased angiogenesis, arteriogenesis, and blood perfusion.¹⁸ Another study showed that curcumin improved angiogenesis and arteriogenesis by promoting the expression of miR-93.¹⁹ • miR-93 increased arteriogenesis and angiogenesis by regulating the expression of multiple genes that coordinated the pathway of apoptosis and cell proliferation.²⁰ • miR-93 inhibited CDKN1A expression at the mRNA and protein expression levels. Hence, promoting arteriogenesis and angiogenesis.²¹	• interferon regulatory factor-9 (IRF9) multiple genes • Cyclin dependent kinase inhibitor 1A (CDKN1A) gene
100	↓	mTOR expression was down-regulated in endothelial cells and vascular smooth muscle cells by overexpression of miR-100, hence it decreased cellular proliferation.²²	mTOR
124-3p	↓	Overexpression of miR-124-3p reduced STAT3 protein expression levels. Hence, mir 124-3p impaired perfusion and angiogenesis.²³	STAT3
126	↑	• CD34Exo contained high level of miR-126-3p which enhanced arteriogenesis and angiogenesis by suppressing the expression of SPRED1. Hence, modulating severals genes expression (VEGF, angiopoietin 1, angiopoietin 2, MMP9, thrombospondin 1, etc).²⁴ • The sustained release of miR-126 loaded with poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) enhanced perfusion and angiogenesis by suppressing the expression of SPRED1.²⁵ Another study showed that miR-126 loaded with Bubble liposomes had the same result.²⁶ • Adipose-Derived Stem Cell Therapeutic Factor Concentrate had a high level of miR-126, which increased perfusion and angiogenesis.²⁷ • MiR-126-3p repaired perfusion and angiogenesis by suppressing the expression of SPRED1 and PIK3R2.²⁸	SPRED1, PIK3R2
130a	↑	Overexpression of miR-130a decreased the expression of MEOX2 and HOXA5 (antiangiogenic genes). Those genes were up-regulated in ischemic muscles of aging mice. Hence, miR-130a improved perfusion and angiogenesis in ischemia related to aging.²⁹	MEOX2 and HOXA5
132/212	↑	MiR-132/212 enhanced the Ras-Mitogen-activated protein kinase MAPK signaling pathway through direct inhibition of Rasa1 and Spred1. The miR-132/212 cluster could enhance arteriogenesis by regulating the Ras-MAPK signaling pathway via direct targeting of the inhibitors Rasa1 and Spred1.³⁰	RASA1, SPRY1, SPRED1
133a	↓	In models of occlusive artery disease with diabetes, overexpression of miR-133a inhibited NO- CGMP angiogenic pathway via targeting GCH1.³¹	GCH1
139-5p	↓	The diabetic condition led to overexpression of miR-139-5p in endothelial cells, thereby it inhibited the c-jun pathway and downregulated the expression of VEGF and PDGF-β. Hence, contributing in the reduction of ECFC migration, proliferation, and tube formation, which consequently diminished endothelial cell survival.³²	c-jun pathway
143-3p	↑	In vivo study showed that increased expression of microRNA 143-3p in response to fluid shear stress could play a role in the reorganization of the extracellular matrix which was important in the process of vascular remodeling through inhibition of V-á2 collagen biosynthesis.³³	V-á2 collagen
146b	↑	miR-146b promoted angiogenesis and arteriogenesis through targets TRAF6 and impeded oxLDL-induced TRAF6-TNFa inflammatory pathway. Therefore, decreased miR-146b expression led to impair arteriogenesis and angiogenesis in hypercholesterolemic conditions.³⁴	TRAF6
146a	↓	Anti microRNA 146a in vivo with femoral artery ligation model showed a 22% increase in collateral artery diameter compared to controls. However, there was no beneficial effect in the process of angiogenesis or muscle regeneration. These effects occurred by upregulation of pro-inflammatory (i.e., NFκB) endothelial cell activation. In addition, arteriogenesis was also possibly mediated via pericollateral Ly6C^hi monocyte proliferation and/or migration.³⁵	NFκB
150	↑	Hypercholesterolemia and exposure to oxidized LDL were associated with increased expression of SRC kinase signaling inhibitor 1 and decreased Src activity. MiR-150 mimics could reduce the expression of SRC kinase signaling inhibitor 1 and restored Src activity and Akt (protein kinase B) activity. Hypercholesterolemia was associated with decreased miR-150 expression, impaired Src signaling pathway, and inefficient neovascularization in response to ischemia. Administration of miR-150 using miR mimics might be a new therapeutic strategy to enhance ischemia-induced neovascularization in atherosclerotic conditions.³⁶	SRCIN-1
155	↑	MicroRNA 155 had the opposite effect as proarteriogenic and antiangiogenic. Its expression in endothelial cells and bone marrow–derived cells was important for arteriogenesis in response to ischemia. MiRNA-155 directly suppressed SOCS1 in monocytes or macrophages, which was a negative feedback regulator of JAK-STAT signaling. Hence, miRNA-155 enhanced monocyte/macrophage rolling, adhesion, migration, and the production of pro-arteriogenic cytokine.³⁷	SOCS1
199a-5p	↓	miR-199a-5p suppressed gene expression of pro-arteriogenic (IKKb, Cav1) and inhibited pericollateral macrophage recruitment. In addition, overexpression of miR-199a reduced collateral artery growth by ±25% (±2.4-fold decrease in conductance) and inhibition of miR-199a increased arteriogenesis by 36% (>3.4-fold conductance increase).³⁸	IKKb, Cav1
210	↑	miR-210 diminished ROS in endothelial cells and ischemic muscle tissue through downregulated P4HB protein levels in EC under a hypoxic environment.³⁹	P4HB
223	↓	miR-223 deterred endothelial cell proliferation by targeting β1 integrin.⁴⁰	β1 integrin
352	↓	Anti miR-352 increased the expression of insulin-like growth factor II receptor (IGF2R), which may contribute in the complex pathway for arterial growth. Furthermore, infusion of antagomir miR-352 could enhance collateral vessel growth.⁴¹	IGF2R
503	↓	Inhibition of miR-503 in ischemic adductor muscle ameliorated post-ischemic blood flow restoration in a mouse model which involved the CDC25A target.⁴²	CDC25A
615-5p	↓	miR-615-5p impeded the VEGF-AKT/eNOS signaling pathway in endothelial cells by directly reduced the level of Ras-associating domain family member 2 (RASSF2) and insulin-like growth factor 2 (IGF2).⁴³	RASSF-2 dan IGF-2
675	↑	Incorporating miR-675 into exosomes encapsulated in silk fibroin hydrogel promoted blood perfusion by inhibiting the TGF-β1/p21 signaling pathway.⁴⁴	TGF-β1/p21 pathway
939-5p	↓	miR-939-5p in exosomes from patients with myocardial ischemia (isc-Exo) inhibited the expression and activity of iNOS, therefore it reduced NO production in endothel. Consequently, it impaired angiogenesis and arteriogenesis.⁴⁵	iNOS

The therapeutic and timing of administration varied among the included studies. Intramuscular injection was the most commonly used (n=21), followed by tail vein (n=5), intra-arterial (n=2), oral (n=1), retro-orbital (n=1), and not clearly explained (n=1). Meanwhile, there were 3 studies that did not use therapeutic agents (owing to genetic modification). Regarding the timing of administration, 11 studies performed repeated administration at different time points: 10 studies administered agent immediately after ligation, 2 studies administered drug one day before ligation, one study delivered agent 30 min before ligation, one study administered agent on day 1 after ligation, one study gave agent on day 7 after ligation. Unfortunately, 7 studies did not clearly state when the agent was administered.

The methods used to evaluate arteriogenesis also varied among the included studies. Imaging techniques were the most commonly used among the studies, from which 31 studies used laser Doppler perfusion imaging, one study used high-resolution laser color Doppler imaging, one study used laser speckle perfusion imaging, one study used contrast-enhanced ultrasound (CEU), one study used periCam perfusion speckle imager, two studies used whole-mount vascular casting, one study used postmortem vascular casting, and one study used postmortem angiogram. Staining methods were also used, and α-smooth muscle actin (α-SMA) staining was the most commonly used method, either by immunohistochemistry or immunofluorescence (n=12). Some of the techniques were combined, of which the most common combination was laser Doppler perfusion imaging and α-smooth muscle actin (α-SMA) staining (n=11). The duration of outcome observation varied among the studies from 7 days to 48 days. The observation time points varied during the observation period.

Table 1 shows that, depending on the specific type of miRNA, some miRNAs need to be upregulated or downregulated to enhance arteriogenesis and vice versa. Some of microRNAs need to be upregulated, namely, miRNA-126-3p, -93, -675, -143-3p, -130a, -210, -146b, -21, -let-7g, -132/212, -150, and 155. In contrast, several microRNAs needed to be downregulated, namely: miRNA-939-5p, -503, -199a-5p, -146a, -92a, -14q32 microRNA gene cluster, -15a/16, -100, -133a, -139-5p, -223, -352, -615-5p, -15b/5p, -124-3p, and 29a. Several microRNAs were loaded when administered to hindlimb ischemia models, namely microRNA-126 was naturally contained in CD34Exo and adipose-derived stem cell therapeutic factor concentrate. MicroRNA-939-5p was abundant in exosomes from patients with myocardial ischemia (isc-Exo). Furthermore, microRNA-21 is abundant in umbilical cord blood-derived mesenchymal stem cells (UCBMSCs). Finally, curcumin modulate the expression of microRNA-93. Table 1 also shows that miR-126 and miR-93 are the most commonly assessed miRNAs in hindlimb ischemia. Regarding the therapeutic target of microRNAs, SPRED1 was the most common, namely miR-126 and -132/212.

Risk of bias assessment

SYRCLE’s risk of bias tool for animal studies was used to assess the risk of bias, and the outcomes are shown in Risk of Bias Assessment.⁵⁹ In most studies, the risk of bias fell into two categories: “unclear” or “high.” In particular, the majority of studies did not specify the adequacy of the generation and application of the allocation sequence, the concealment of allocation to different groups during the experiment, or the random housing or selection of animals for outcome assessment, whether investigators were blinded to the interventions received by each animal, or whether the outcome assessor was blinded.

Discussion

This study aimed to systematically search and review the literature on the therapeutic potential of microRNAs in limb ischemia. To date, only in vivo studies have evaluated the potential role of miRNAs in arteriogenesis. Depending on the specific type, the expression could lead to enhanced or decreased arteriogenesis. The following miRNAs were upregulated to enhance arteriogenesis: miRNA-126-3p, -93, -675, -143-3p, -130a, -210, -146b, -21, -let-7g, -132/212, -150, and 155. Meanwhile, microRNAs needed to be downregulated, namely: miRNA-939-5p, -503, -199a-5p, -146a, -92a, -14q32 microRNA gene cluster, -15a/16, -100, -133a, -139-5p, -223, -352, -615-5p, -15b/5p, -124-3p, and 29a. These miRNAs have different target sites in arteriogenesis, with miRNA-126 being the most studied ( Figure 1). The high heterogeneity among selected studies in terms of microRNA used, techniques for inducing limb ischemia, administration methods in intervention and control groups, and techniques for evaluating arteriogenesis as well as time-points of outcome assessment, hindered the performance of a meta-analysis.

Figure 1. Proposed mechanism of several microRNAs in arteriogenesis process.

In this study, mice were the most commonly used limb ischemia models because of their practical aspects and their similarity to humans in terms of neovascularization patterns and genetic aspect.⁴⁶^–⁴⁸ Moreover the availability of several transgenic mice might be the reason for preferring the use of mice, as shown in these studies. Unfortunately, only two studies were performed in immunocompromised mice, since miRNAs might stimulate immune responses, including macrophages and T cells, and thus might affect the outcome of arteriogenesis.⁴⁶^,⁴⁹ The technical approach for inducing limb ischemia was also widely varied in this study, which might affect the arteriogenesis outcome. Double ligation of the iliac and femoral arteries causes severe ischemia rather than single ligation. Moreover, the ligation approach is better than electrocoagulation since recoil will not occur.⁴⁶ Concurrent ligation and excision methods will increase the severity level of ischemia.⁵⁰ Regarding to sex animal models, most of the selected studies used male due to hinder the effects of estrogen on vascular regrowth.⁵¹ Unfortunately, several studies did not clearly declare animal sex, and two studies in rabbits and mice used female sex.

Imaging techniques can assess arteriogenesis anatomically or functionally.⁵² In this study, most studies used a functional approach such as laser doppler perfusion imaging which assesses restoration of tissue perfusion, equivalent to the sign of effective arteriogenesis.⁵² The anatomical approaches used in this study were whole mount vascular casting, postmortem vascular casting, and postmortem angiogram. A combination of anatomical and functional approaches can provide more insight into both the visual and quantitative extent of circulation formation and its functional effectiveness.⁵² In this study, miR-199a-5p and miR-146 were assessed using both methods. In addition to imaging methods, histological staining has also been used to assess arteriogenesis.⁵³ Unfortunately, none of these studies used a combination of anatomical, functional imaging, and histological staining. Such a combination may yield more reliable results.

In general, the arteriogenesis process requires endothelial and smooth muscle cell proliferation, in which growth factor is crucial to proliferate smooth muscle cells. In the later process, adventitia remodeling through activation and proliferation of fibroblast caused enlargement of lumen vessels.⁹ Nevertheless, the exact molecular mechanisms involved in all multifactorial arteriogenesis process is still not fully understood.⁵⁴ However, recent evidence showed that microRNA is involved in signaling pathways related to arteriogenesis.⁸ As shown in this study, microRNAs affect several pathways related to arteriogenesis, such as Ras-MAPK, TGF-β1/p21, AKT3/eNOS, and JAK-STAT signaling pathway. Table 1 also shows that miRNAs can lead to arteriogenesis by directly targeting several genes and proteins.

VEGF-A is essential for endothelial proliferation by binding to VEGFR-2 to stimulate intracellular signaling process.⁵⁵ That evidence is supported in this study, in which promoting mir126 and letting 7 g as well as inhibiting mir 15a/16 activate VEGF, leading to arteriogenesis. Another study showed that an increase in miR-139-5p expression in diabetic mice led to downregulation of VEGF, consequently decreasing arteriogenesis. Moreover, miR-223, 100, and 93 also affect cell proliferation by binding to their respective targets, ultimately affecting arteriogenesis.

Macrophage recruitment is essential for arteriogenesis. Activated macrophages produce TNF-α, growth factor, and chemokines and recruit more monocytes, thereby promoting arteriogenesis.⁹ Those results were supported by the results of the present study, in which miRNAs 199a-5p, 146a, and 155 had a role in macrophage recruitment. Moreover, macrophage polarization to an anti-inflammatory macrophage type 2 in ischemic muscle, shown by miR-93, is essential during post-ischemic vascular injury and repair, since M2 macrophages are pro-angiogenic.⁵⁶

In this study, the delivery approach varied; however, most of them used intramuscular injections. However, all delivery approaches, including tail vein, intravenous injection, oral, retro-orbital, and intra-arterial, showed positive results related to arteriogenesis. These results suggested that miRNAs have systemic effects. Depending on the specific type of microRNA, all studies that used concomitant conditions such as diabetic and hypercholesterolemic mice showed positive results in arteriogenesis. These results might suitably explain the use of microRNAs in humans, since CLTI is strongly associated with cardiovascular risk factors, such as diabetes mellitus and dyslipidemia.⁵⁷ Aging mice might also be analogous to patients with CLTI due to the increasing number of CLTI in the older population.⁵⁸

The application of SYRCLE’s risk of bias tool to assess animal studies revealed a prevalent “unclear” or “high” risk of bias across the majority of cases. These studies exhibited deficiencies in essential aspects, such as the generation and application of allocation sequences, allocation concealment, randomization of housing, selection for outcome assessment, and blinding of investigators and outcome assessors. Therefore, these results should be cautiously interpreted.

Our systematic review had several limitations. First, we reviewed only studies published in English. Second, all research conducted in animal models had high heterogeneity related to inducing hindlimb ischemia, intervention, and outcome assessment methods. Therefore, clinical studies in humans are required to verify the effect of miRNA modulation using mimic and/or inhibitor miRNAs in patients with chronic limb-threatening ischemia.

Conclusion

Taken together, our review identifies several miRNAs in preclinical models that show potential for therapeutic purposes to enhance arteriogenesis in patients with chronic limb-threatening ischemia. Hence, a study involving patients with chronic limb-threatening ischemia is required.

Data availability

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Extended data

Figshare: The Role of Therapeutic MicroRNA in Arteriogenesis Process in Limb Ischemia: A Systematic Review. DOI: https://doi.org/10.6084/m9.figshare.25036163.v3.⁵⁹

This project contains the following extended data:

• PRISMA Flowchart for The Systematic Review
• Table 1. Characteristics of Study
• Risk of Bias Assessment
• Completed PRISMA checklist

Data are available under the terms of the Creative Commons Zero CC0.

Acknowledgements

We thank Hariadi, Yohanes William, Tinanda Tarigan, Afif Ramadhan, and Jessica Eve from Department of Cardiology and Vascular Medicine, Faculty of Medicine, Public Health and Nursing Gadjah Mada University, Sleman, Indonesia for their technical support, all of whom approved their inclusion.

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Version 2

VERSION 2 PUBLISHED 09 May 2024

Author details Author details

Dyah Wulan Anggrahini
Roles: Data Curation, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing

Sofia Mubarika Haryana
Roles: Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing

Budi Yuli Setianto
Roles: Methodology, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

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The author(s) declared that no grants were involved in supporting this work.

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https://doi.org/10.12688/f1000research.147482.2

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Ismail MT, Anggrahini DW, Haryana SM and Setianto BY. The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review [version 2; peer review: 1 approved]. F1000Research 2024, 13:470 (https://doi.org/10.12688/f1000research.147482.2)

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Reviewer Report 26 Nov 2024

Brian H Annex, Medical College of Georgia at Augusta University, Augusta, Georgia, USA

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https://doi.org/10.5256/f1000research.174708.r340588

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Reviewer Report 29 Oct 2024

Brian H Annex, Medical College of Georgia at Augusta University, Augusta, Georgia, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.161682.r326630

The manuscript by Asmail et al. is a systematic/literature review of micro-RNA reported to be related to peripheral arterial disease. In general, the limitations of such reviews are well known but the benefits are in providing a single go-to source of information. Before this reviewer lists a series of relatively minor comments/areas that require clarification, one request for additional (new) data will be listed.

1) Often in a study that focuses on a microRNA, other microRNAs are also examined. If a publication focused on miR-A (letter intentionally used to avoid confusion) were other miRs that ultimately ended in this report also studied? For example, if in the study of miR-A, miR-B and miR-C (where miR-B and miR-C ultimately made this report) were also found to differentially regulated, that would provide a validation. If several reports of course even better. It of course could turn out that study of the regulation miR-B in teh report on miR-A could be different. That would be valuable as well. Likely, in many, this may not be possible but this could expand the value of the review.

More minor comments:
1) Introduction, paragraph 2, last sentence. Given that no agent has definitely driven angiogiogenesis in CLTI, this sentence may not be completely accurate. To make the statement one would need an agent that promoted angiogenesis, not arteriogenesis, and had no therapeuitc effect.

2) Introduction, paragraph 3, miRs do not signal unless the authors are referring to miR-protein interactions.

3) Methods, when the two "selectors" disagreed initially on inclusion -- how often was the agreement for and how often against inclusion.

4) Curcumin was mentioned. Was this referring to the dietary supplement? Would a miR be stable through the GI track?

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Partly
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

Partly
Are the conclusions drawn adequately supported by the results presented in the review?

Partly
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

No

Competing Interests: I am founder of start-up company focusing on miR-93 for PAD. I have founder shares in this start-up company.

Reviewer Expertise: Human and experimental peripheral arterial disease including but not limited to non-coding RNAs.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Author Response 14 Nov 2024

Muhamad Taufik Ismail, Cardiology and Vascular Medicine, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, 55281, Indonesia

14 Nov 2024

Author Response

Dear Brian H Annex, thank you for your time and insightful comments. In our study, of the 36 studies reviewed, 35 directly employed specific miRs or agents containing/enriched with/affecting specific ... Continue reading Dear Brian H Annex, thank you for your time and insightful comments. In our study, of the 36 studies reviewed, 35 directly employed specific miRs or agents containing/enriched with/affecting specific miRs, and therefore did not assess other miRs. One study by Li did examine additional miRs using microarray technology; however, only the miRs with a significant role in arteriogenesis were reported. Some studies validate each other due to shared regulatory pathways, such as with miR-93 and miR-126. No studies presented conflicting findings.

Here is the response for addressing minor comments:
1. Our aim was to emphasize the general importance of arteriogenesis over angiogenesis in CLTI, as highlighted by Caicedo et al. According to the 2019 ESVS guidelines on CLTI, agents such as stem cells have been shown in clinical trials to enhance angiogenesis, however, they have yet to yield clinical benefits in terms of reducing amputation rates or mortality. This finding underscores the need to prioritize arteriogenesis rather than angiogenesis in this context.
2. We sincerely appreciate your insightful comments and suggestions for revising the paper. We have revised the sentence to clarify the role of miRNAs in influencing signaling pathways rather than directly "signaling." This revision aims to reflect the regulatory role of miRNAs in modulating pathway activity without implying direct signaling.
3. Thank you for your question. In cases where the two reviewers (MT and DA) initially disagreed on inclusion, an additional review by senior reviewers (BY and SM) was conducted to reach a consensus. In 80% of the journals, both reviewers shared the same inclusion criteria, while in 20% of cases, differing opinions required a final decision from the senior reviewers.
4. Based on the article, curcumin is categorized as a dietary supplement because it is a naturally occurring compound derived from turmeric and was administered orally, similar to the typical consumption of dietary supplements. In this study, curcumin is used to investigate its therapeutic effects, showing that while curcumin does not contain miRNAs necessary for arteriogenesis, it modulates the expression of endogenous miRNAs to impact molecular pathways, specifically targeting miRNA pathways within cells. I will incorporate these points in revising the manuscript. It is well-established that many naked miRNAs degrade in the gastrointestinal (GI) tract due to exposure to enzymes, stomach acidity, and intestinal nucleases.
Dear Brian H Annex, thank you for your time and insightful comments. In our study, of the 36 studies reviewed, 35 directly employed specific miRs or agents containing/enriched with/affecting specific miRs, and therefore did not assess other miRs. One study by Li did examine additional miRs using microarray technology; however, only the miRs with a significant role in arteriogenesis were reported. Some studies validate each other due to shared regulatory pathways, such as with miR-93 and miR-126. No studies presented conflicting findings.

Here is the response for addressing minor comments:
1. Our aim was to emphasize the general importance of arteriogenesis over angiogenesis in CLTI, as highlighted by Caicedo et al. According to the 2019 ESVS guidelines on CLTI, agents such as stem cells have been shown in clinical trials to enhance angiogenesis, however, they have yet to yield clinical benefits in terms of reducing amputation rates or mortality. This finding underscores the need to prioritize arteriogenesis rather than angiogenesis in this context.
2. We sincerely appreciate your insightful comments and suggestions for revising the paper. We have revised the sentence to clarify the role of miRNAs in influencing signaling pathways rather than directly "signaling." This revision aims to reflect the regulatory role of miRNAs in modulating pathway activity without implying direct signaling.
3. Thank you for your question. In cases where the two reviewers (MT and DA) initially disagreed on inclusion, an additional review by senior reviewers (BY and SM) was conducted to reach a consensus. In 80% of the journals, both reviewers shared the same inclusion criteria, while in 20% of cases, differing opinions required a final decision from the senior reviewers.
4. Based on the article, curcumin is categorized as a dietary supplement because it is a naturally occurring compound derived from turmeric and was administered orally, similar to the typical consumption of dietary supplements. In this study, curcumin is used to investigate its therapeutic effects, showing that while curcumin does not contain miRNAs necessary for arteriogenesis, it modulates the expression of endogenous miRNAs to impact molecular pathways, specifically targeting miRNA pathways within cells. I will incorporate these points in revising the manuscript. It is well-established that many naked miRNAs degrade in the gastrointestinal (GI) tract due to exposure to enzymes, stomach acidity, and intestinal nucleases.
Competing Interests: We confirm that there are no competing interests that could be construed to influence our assessment of the article’s or the peer review report’s validity or significance. Close
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Author Response 14 Nov 2024

Muhamad Taufik Ismail, Cardiology and Vascular Medicine, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, 55281, Indonesia

14 Nov 2024

Author Response

Dear Brian H Annex, thank you for your time and insightful comments. In our study, of the 36 studies reviewed, 35 directly employed specific miRs or agents containing/enriched with/affecting specific ... Continue reading Dear Brian H Annex, thank you for your time and insightful comments. In our study, of the 36 studies reviewed, 35 directly employed specific miRs or agents containing/enriched with/affecting specific miRs, and therefore did not assess other miRs. One study by Li did examine additional miRs using microarray technology; however, only the miRs with a significant role in arteriogenesis were reported. Some studies validate each other due to shared regulatory pathways, such as with miR-93 and miR-126. No studies presented conflicting findings.

Here is the response for addressing minor comments:
1. Our aim was to emphasize the general importance of arteriogenesis over angiogenesis in CLTI, as highlighted by Caicedo et al. According to the 2019 ESVS guidelines on CLTI, agents such as stem cells have been shown in clinical trials to enhance angiogenesis, however, they have yet to yield clinical benefits in terms of reducing amputation rates or mortality. This finding underscores the need to prioritize arteriogenesis rather than angiogenesis in this context.
2. We sincerely appreciate your insightful comments and suggestions for revising the paper. We have revised the sentence to clarify the role of miRNAs in influencing signaling pathways rather than directly "signaling." This revision aims to reflect the regulatory role of miRNAs in modulating pathway activity without implying direct signaling.
3. Thank you for your question. In cases where the two reviewers (MT and DA) initially disagreed on inclusion, an additional review by senior reviewers (BY and SM) was conducted to reach a consensus. In 80% of the journals, both reviewers shared the same inclusion criteria, while in 20% of cases, differing opinions required a final decision from the senior reviewers.
4. Based on the article, curcumin is categorized as a dietary supplement because it is a naturally occurring compound derived from turmeric and was administered orally, similar to the typical consumption of dietary supplements. In this study, curcumin is used to investigate its therapeutic effects, showing that while curcumin does not contain miRNAs necessary for arteriogenesis, it modulates the expression of endogenous miRNAs to impact molecular pathways, specifically targeting miRNA pathways within cells. I will incorporate these points in revising the manuscript. It is well-established that many naked miRNAs degrade in the gastrointestinal (GI) tract due to exposure to enzymes, stomach acidity, and intestinal nucleases.
Dear Brian H Annex, thank you for your time and insightful comments. In our study, of the 36 studies reviewed, 35 directly employed specific miRs or agents containing/enriched with/affecting specific miRs, and therefore did not assess other miRs. One study by Li did examine additional miRs using microarray technology; however, only the miRs with a significant role in arteriogenesis were reported. Some studies validate each other due to shared regulatory pathways, such as with miR-93 and miR-126. No studies presented conflicting findings.

Here is the response for addressing minor comments:
1. Our aim was to emphasize the general importance of arteriogenesis over angiogenesis in CLTI, as highlighted by Caicedo et al. According to the 2019 ESVS guidelines on CLTI, agents such as stem cells have been shown in clinical trials to enhance angiogenesis, however, they have yet to yield clinical benefits in terms of reducing amputation rates or mortality. This finding underscores the need to prioritize arteriogenesis rather than angiogenesis in this context.
2. We sincerely appreciate your insightful comments and suggestions for revising the paper. We have revised the sentence to clarify the role of miRNAs in influencing signaling pathways rather than directly "signaling." This revision aims to reflect the regulatory role of miRNAs in modulating pathway activity without implying direct signaling.
3. Thank you for your question. In cases where the two reviewers (MT and DA) initially disagreed on inclusion, an additional review by senior reviewers (BY and SM) was conducted to reach a consensus. In 80% of the journals, both reviewers shared the same inclusion criteria, while in 20% of cases, differing opinions required a final decision from the senior reviewers.
4. Based on the article, curcumin is categorized as a dietary supplement because it is a naturally occurring compound derived from turmeric and was administered orally, similar to the typical consumption of dietary supplements. In this study, curcumin is used to investigate its therapeutic effects, showing that while curcumin does not contain miRNAs necessary for arteriogenesis, it modulates the expression of endogenous miRNAs to impact molecular pathways, specifically targeting miRNA pathways within cells. I will incorporate these points in revising the manuscript. It is well-established that many naked miRNAs degrade in the gastrointestinal (GI) tract due to exposure to enzymes, stomach acidity, and intestinal nucleases.
Competing Interests: We confirm that there are no competing interests that could be construed to influence our assessment of the article’s or the peer review report’s validity or significance. Close
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Brian H Annex, Medical College of Georgia at Augusta University, Augusta, Georgia, USA

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Approved

the response was adequate.
I have no further comments.

Competing Interests

I am founder of start-up company focusing on miR-93 for PAD. I have founder shares in this start-up company.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Brian H Annex, Medical College of Georgia at Augusta University, Augusta, Georgia, USA

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Approved With Reservations

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Partly
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

Partly
Are the conclusions drawn adequately supported by the results presented in the review?

Partly
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

No

Competing Interests

I am founder of start-up company focusing on miR-93 for PAD. I have founder shares in this start-up company.

Reviewer Expertise

Human and experimental peripheral arterial disease including but not limited to non-coding RNAs.

Respond to this report

Responses (1)

Author Response

14 Nov 2024

Muhamad Taufik Ismail, Cardiology and Vascular Medicine, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, 55281, Indonesia

Dear Brian H Annex, thank you for your time and insightful comments. In our study, of the 36 studies reviewed, 35 directly employed specific miRs or agents containing/enriched with/affecting specific miRs, and therefore did not assess other miRs. One study by Li did examine additional miRs using microarray technology; however, only the miRs with a significant role in arteriogenesis were reported. Some studies validate each other due to shared regulatory pathways, such as with miR-93 and miR-126. No studies presented conflicting findings.

Here is the response for addressing minor comments:
1. Our aim was to emphasize the general importance of arteriogenesis over angiogenesis in CLTI, as highlighted by Caicedo et al. According to the 2019 ESVS guidelines on CLTI, agents such as stem cells have been shown in clinical trials to enhance angiogenesis, however, they have yet to yield clinical benefits in terms of reducing amputation rates or mortality. This finding underscores the need to prioritize arteriogenesis rather than angiogenesis in this context.
2. We sincerely appreciate your insightful comments and suggestions for revising the paper. We have revised the sentence to clarify the role of miRNAs in influencing signaling pathways rather than directly "signaling." This revision aims to reflect the regulatory role of miRNAs in modulating pathway activity without implying direct signaling.
3. Thank you for your question. In cases where the two reviewers (MT and DA) initially disagreed on inclusion, an additional review by senior reviewers (BY and SM) was conducted to reach a consensus. In 80% of the journals, both reviewers shared the same inclusion criteria, while in 20% of cases, differing opinions required a final decision from the senior reviewers.
4. Based on the article, curcumin is categorized as a dietary supplement because it is a naturally occurring compound derived from turmeric and was administered orally, similar to the typical consumption of dietary supplements. In this study, curcumin is used to investigate its therapeutic effects, showing that while curcumin does not contain miRNAs necessary for arteriogenesis, it modulates the expression of endogenous miRNAs to impact molecular pathways, specifically targeting miRNA pathways within cells. I will incorporate these points in revising the manuscript. It is well-established that many naked miRNAs degrade in the gastrointestinal (GI) tract due to exposure to enzymes, stomach acidity, and intestinal nucleases.

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Competing Interests

We confirm that there are no competing interests that could be construed to influence our assessment of the article’s or the peer review report’s validity or significance.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review

Abstract

Background

Methods

Results

Conclusion

Registration

Keywords

Revised Amendments from Version 1

Introduction

Methods

Search strategy

Eligibility criteria

Data extraction

Risk of bias assessment

Results

Search results

Study characteristics

Table 1. MicroRNAs involved in arteriogenesis.

Risk of bias assessment

Discussion

Figure 1. Proposed mechanism of several microRNAs in arteriogenesis process.

Conclusion

Data availability

Underlying data

Extended data

Acknowledgements

References

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