A review of the current state in neointimal hyperplasia development following endovascular intervention and minor emphasis on new horizons in immunotherapy.

Endovascular strategies play a vital role in the treatment of peripheral arterial disease (PAD). However, luminal loss or restenosis after endovascular intervention remains a significant challenge. The main underlying mechanisms are negative vascular remodeling and elastic recoil in balloon angioplasty. During stenting, the main reason for this complex is neointimal proliferation. Endothelial cell injury due to endovascular intervention initiates a series of molecular events, such as overexpression of growth factors, cytokine secretion, and adhesion molecules. These induce platelet activation and inflammatory processes, which trigger the proliferation and migration of vascular smooth muscle cells into the intima, resulting in neointimal hyperplasia. During this process, PAD progression is mainly caused by chronic inflammation, in which macrophages play a central role. Of the current strategies, drug release interventions aim to suppress restenosis using antiproliferative drugs, such as sirolimus and paclitaxel, during drug release. These drugs inhibit vascular reendothelialization and reduce late in-stent restenosis. For this reason, immunotherapy can be considered an important alternative. Interventions that polarize macrophages to the M2 subtype are particularly important, as they shape the immune response in an anti-inflammatory direction and contribute to tissue repair. However, there are several challenges to overcome, such as localizing antiproliferative or polarizing agents only to areas of vascular injury. This review discusses, based on the early study observations, immunotherapeutic approaches to prevent restenosis after endovascular intervention for the treatment of PAD.