Atherosclerosis is a leading cause of morbidity and mortality globally. Currently, many procedures are performed by interventionists and vascular surgeons to treat atherosclerosis, such as balloon angioplasty with or without stenting, endarterectomy, or surgical bypass grafting. However, despite the benefits, these interventions fail from restenosis due to neointimal hyperplasia (NIH). In a normal vasculature, smooth muscle cells (SMC) are found in the tunica media, and they are quiescent with minimal turnover and contractile phenotype. Neointimal hyperplasia refers to post-intervention, pathological, vascular remodeling due to the proliferation and migration of vascular smooth muscle cells into the tunica intima layer, resulting in vascular wall thickening and the gradual loss of luminal patency which may lead to the return of vascular insufficiency symptoms. [1][2] SMC in neointimal hyperplasia lose contractile phenotype, and they differentiate into secretory phenotype predominantly. These modified SMC secrete the growth factors, growth factor receptors, extracellular matrix, proteinases, and inflammatory mediators responsible for neointimal hyperplasia. Many vascular interventions put vessels at risk of injury, leading to restenosis due to activation of the inflammatory cascade and cellular recruitment. It is most evident in "in-stent restenosis" after the plain old balloon angioplasty (POBA) without stenting and percutaneous coronary intervention with bare-metal stenting. Metallic stents were necessary to counteract acute vascular recoil after POBA, but after serving this purpose, long-term in situ metallic platform injure the vascular wall and sets in chronic inflammation and hyperplasia of the vascular intimal layer. Other vascular manipulation also may result in vessel injury, leading to neointimal hyperplasia.

There are two types of neointimal hyperplasia.

1. Arterial neointimal hyperplasia secondary to arterial manipulation in endarterectomy or angioplasty. [3]
2. Venous graft associated neointimal hyperplasia secondary to coronary artery bypass grafting or arteriovenous grafting/ fistula formation. [4]

Vascular wall injury may be due to manipulation by any of the following procedures:

• Use of angioplasty catheter and balloon inflation during the angioplasty.
• Use of an embolectomy catheter.
• Vascular endarterectomy. 
• Small target veins used in arteriovenous fistula creation. 
• Coronary vein grafting or coronary artery bypass grafting (CABG).

• The patency rate of the venous graft used during CABG is 80% at one year and 60% at five years. A saphenous venous graft (SVG) is more prone to intimal hyperplasia and stenosis than an internal mammary artery graft. However, late-onset occlusion of SVG after five years of grafting is almost always due to neo-atherosclerosis. 
• Arteriovenous (AV) fistula or graft is used as a vascular access site for hemodialysis in patients with end-stage renal disease (ESRD) on dialysis. Arteriovenous (AV) fistula or graft failure rate varies between 30% to 60% at one year. Recent studies have indicated that neointimal hyperplasia is the most common underlying pathology in 30% to 60% of AV grafts or fistula failures followed by vascular thrombosis.

The events leading to neointimal hyperplasia can be broadly classified into the following:

• Endothelial dysfunction and activation
• Platelet activation and thrombus formation
• Leucocyte recruitment
• Smooth muscle cell migration and proliferation

The primary pathology is the proliferation and migration of smooth muscle cells (SMCs) in the tunica intima layer. The triggering step is endothelial damage or dysfunction (ED) due to vascular injury, which can occur secondary to a vascular wall stretching during balloon angioplasty, vascular manipulation during carotid endarterectomy, or venous graft implantation during arteriovenous fistula formation or coronary bypass grafting. [1] ED leads to endothelial activation and decreases the production of nitrous oxide (NO) due to the dysregulation of endothelial nitric oxide synthase (ENOS). [5][6] When platelets come in contact with activated endothelial cells, it forms a platelet-rich thrombus. An inflammatory cascade begins at the vascular injury site, and leukocytes demarginate from the bloodstream and reach sub-endothelial thrombus. Oxidative stress promotes the expression of endothelial adhesion molecules, such as vascular cell adhesion molecules, that help recruitment and migration of monocytes into the subendothelial area. [7][2]

Matrix metalloproteinases are key enzymes that cause the breakdown of extracellular matrix proteins, such as collagen and elastin, and facilitate the migration of vascular SMCs across internal elastic lamina in neointimal hyperplasia formation. [8]It is also noted in arteriovenous grafts studies that SMCs can alternately originate from fibroblasts from vascular adventitia or bone marrow progenitor cells. [2][9] Once SMCs migrate at the vascular injury site intimal layer, they go through a phenotypic transition from predominantly contractile to secretory type SMCs.

In both arterial and venous neointimal hyperplasia, there is SMC and fibroblast accumulation in the tunica intima layer with extracellular matrix (ECM) or collagen deposition. On immunohistochemistry studies, vascular samples with neointimal hyperplasia show multi-layered SMCs, which stain positive for alpha-smooth muscle actin, endothelial cells staining positive for anti-von Willebrand factor antibodies, fibroblasts which secrete ECM, lymphocytes, and macrophages. The excessive cellular deposition results in the expansion of the intimal layer and loss of the luminal area. [10] Tunica media layer in arterial neointimal hyperplasia tends to remain thin despite the increased thickness of the intimal layer. This is in contrast to vein graft adaptation, where there is also a concurrent expansion of the tunica media layer. [4][11][12][13]