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Macrophage Polarization as a Novel Therapeutic Target for Endovascular Intervention in Peripheral Artery Disease.

ABSTRACT: Peripheral artery disease (PAD) has a significant impact on human health, affecting 200 million people globally. Advanced PAD severely diminishes quality of life, affecting mobility, and in its most severe form leads to limb amputation and death. Treatment of PAD is among the least effective of all endovascular procedures in terms of long-term efficacy. Chronic inflammation is a key driver of PAD; however, stents and coated balloons eluting antiproliferative drugs are most commonly used. As a result, neither stents nor coated balloons produce durable clinical outcomes in the superficial femoral artery, and both have recently been associated with significantly increased mortality. This review summarizes the most common clinical approaches and limitations to treating PAD and highlights the necessity to address the underlying causes of inflammation, identifying macrophages as a novel therapeutic target in the next generation of endovascular PAD intervention.

SUBMITTER: Tan RP

PROVIDER: S-EPMC8385566 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Macrophage Polarization as a Novel Therapeutic Target for Endovascular Intervention in Peripheral Artery Disease.

Tan Richard P RP Ryder Isabelle I Yang Nianji N Lam Yuen Ting YT Santos Miguel M Michael Praveesuda L PL Robinson David A DA Ng Martin K MK Wise Steven G SG

JACC. Basic to translational science 20210723 8

Peripheral artery disease (PAD) has a significant impact on human health, affecting 200 million people globally. Advanced PAD severely diminishes quality of life, affecting mobility, and in its most severe form leads to limb amputation and death. Treatment of PAD is among the least effective of all endovascular procedures in terms of long-term efficacy. Chronic inflammation is a key driver of PAD; however, stents and coated balloons eluting antiproliferative drugs are most commonly used. As a re ...[more]

PMID: 34466756

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Project description:BackgroundAtherosclerotic occlusions decrease blood flow to the lower limbs, causing ischemia and tissue loss in patients with peripheral artery disease (PAD). No effective medical therapies are currently available to induce angiogenesis and promote perfusion recovery in patients with severe PAD. Clinical trials aimed at inducing vascular endothelial growth factor (VEGF)-A levels, a potent proangiogenic growth factor to induce angiogenesis, and perfusion recovery were not successful. Alternate splicing in the exon-8 of VEGF-A results in the formation of VEGFxxxa (VEGF165a) and VEGFxxxb (VEGF165b) isoforms with existing literature focusing on VEGF165b's role in inhibiting vascular endothelial growth factor receptor 2-dependent angiogenesis. However, we have recently shown that VEGF165b blocks VEGF-A-induced endothelial vascular endothelial growth factor receptor 1 (VEGFR1) activation in ischemic muscle to impair perfusion recovery. Because macrophage-secreted VEGF165b has been shown to decrease angiogenesis in peripheral artery disease, and macrophages were well known to play important roles in regulating ischemic muscle vascular remodeling, we examined the role of VEGF165b in regulating macrophage function in PAD.MethodsFemoral artery ligation and resection were used as an in vivo preclinical PAD model, and hypoxia serum starvation was used as an in vitro model for PAD. Experiments including laser-Doppler perfusion imaging, adoptive cell transfer to ischemic muscle, immunoblot analysis, ELISAs, immunostainings, flow cytometry, quantitative polymerase chain reaction analysis, and RNA sequencing were performed to determine a role of VEGF165b in regulating macrophage phenotype and function in PAD.ResultsFirst, we found increased VEGF165b expression with increased M1-like macrophages in PAD versus non-PAD (controls) muscle biopsies. Next, using in vitro hypoxia serum starvation, in vivo pre clinical PAD models, and adoptive transfer of VEGF165b-expressing bone marrow-derived macrophages or VEGFR1+/- bone marrow-derived macrophages (M1-like phenotype), we demonstrate that VEGF165b inhibits VEGFR1 activation to induce an M1-like phenotype that impairs ischemic muscle neovascularization. Subsequently, we found S100A8/S100A9 as VEGFR1 downstream regulators of macrophage polarization by RNA-Seq analysis of hypoxia serum starvation-VEGFR1+/+ versus hypoxia serum starvation-VEGFR1+/- bone marrow-derived macrophages.ConclusionsIn our current study, we demonstrate that increased VEGF165b expression in macrophages induces an antiangiogenic M1-like phenotype that directly impairs angiogenesis. VEGFR1 inhibition by VEGF165b results in S100A8/S100A9-mediated calcium influx to induce an M1-like phenotype that impairs ischemic muscle revascularization and perfusion recovery.

Project description:IntroductionPeripheral artery disease (PAD) is a major risk factor for cardiovascular morbidity and mortality, despite surgical and endovascular treatments. Emerging evidence supports the use of immediate antithrombotic medications after endovascular intervention for PAD, however, there is a lack of consensus regarding choice and duration of antithrombotic therapy. Prescriber decision-making is a complex process, with prior studies demonstrating patient factors can influence variability in antithrombotic therapy for PAD. However, it remains unclear the relative contribution of these factors. This paper describes a planned study that aims to (1) determine the influence of patient factors on clinician preference for antithrombotic therapy following endovascular intervention and (2) compare differences in prescribing preferences between consultant vascular surgeons and trainees.Methods and analysisThis cross-sectional survey will evaluate antithrombotic prescribing choices using a discrete choice experiment (DCE) that has been developed and piloted for this study. A list of attributes and levels was generated using a mixed-methods approach. This included an extensive literature review and semistructured interviews with prescribing clinicians. Following final selection of included attributes, specialised software was used to construct a D-efficient design for the DCE questionnaire. The electronic questionnaire will be administered to vascular trainees and consultant surgeons across Australia. These data will be analysed using multinomial logistic regression, treating the decision to prescribe antithrombotic therapy as a function of both the attributes of the two alternatives, as well as characteristics of the respondent. Latent class analysis will be used to explore heterogeneity of responses.Ethics and disseminationEthics approval was obtained from the University of Sydney Human Ethics committee (2023/474). The results of this study will be published in peer-reviewed journals and presented at national vascular surgical conferences. These results will be used to improve understanding how clinicians make prescribing decisions and to inform future strategy to enhance guideline-directed prescribing.

Dataset Information

Macrophage Polarization as a Novel Therapeutic Target for Endovascular Intervention in Peripheral Artery Disease.

Publications

Macrophage Polarization as a Novel Therapeutic Target for Endovascular Intervention in Peripheral Artery Disease.

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