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.

Keywords: BMS, bare-metal stent; CAD, coronary artery disease; DES, drug-eluting stent; FP, femoropopliteal; IL, interleukin; MI, myocardial infarction; PAD, peripheral artery disease; PTA, percutaneous transluminal angioplasty; SFA, superficial femoral artery; TGF, transforming growth factor; TNF, tumor necrosis factor; drug-eluting balloon; drug-eluting stent; endovascular intervention; macrophage polarization; paclitaxel; peripheral arterial disease; vascular healing; vascular inflammation.

Graphical abstract

Figure 1

PAD Pathophysiology vs Intervention Failure Revascularization of occlusive lesions in peripheral artery disease (PAD) becomes more challenging with decreasing arterial diameter (left) and increasing lesion length (right).

Figure 2

Mechanisms of Macrophage-Driven Restenosis Following Balloon Injury Cross-section of balloon injured blood vessel showing M1 macrophages coordinating immune cell recruitment in response to endothelial damage as well as secretion of proinflammatory cytokines that stimulate smooth muscle cell proliferation into the intima. M2 polarization halts immune cell recruitment through the release of anti-inflammatory cytokines and facilitates endothelial repair through the release of proangiogenic factors. ATP = adenosine triphosphate; FGF = fibroblast growth factor; HSP = heat shock protein; IL = interleukin; SMC = smooth muscle cell; TGF = transforming growth factor; TNF = tumor necrosis factor; VEGF = vascular endothelial growth factor.

Central Illustration

Macrophage Polarization as an Alternative Target for Improved Long-Term Outcomes of Peripheral Artery Disease Intervention Current drug-eluting peripheral artery disease interventions relying on antiproliferative drugs (eg, sirolimus, paclitaxel) suppress restenosis for the duration of drug elution but do not address underlying vessel injury and inflammation driven by M1 macrophages (Top). Additionally, current immunotherapy approaches focus solely on targeting individual cytokines sustaining vascular injury but are similarly only effective as long as the drug is eluted. Polarization of macrophages toward anti-inflammatory/tissue reparative M2 phenotypes represents a potentially more effective and long-lasting approach to suppress vascular inflammation by repairing injured vessels (Bottom).

Figure 3

Emerging Localized Delivery Platforms for Peripheral Artery Disease Intervention The effectiveness of M2 macrophage polarizing agents (blue circles) will rely on localized delivery to injured vessels or damaged endothelium for lasting suppression of restenosis. (A) Device coatings comprise covalently immobilized agents can polarize both circulating monocytes and macrophages as well as tissue resident macrophages. (B) Slow-release platforms consisting of degradable polymers or passively adsorbed can release agents not only locally into the vessel well, but also into systemic circulation. (C) Targeted systemic delivery strategies may involve nanoparticles decorated with targeting ligands to localize agents only to areas of vessel injury. SMC = smooth muscle cell.