Atherosclerosis is a leading cause of morbidity and mortality globally. Currently, many interventions are done 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 resident of tunica media, and they are quiescent with minimal turnover and contractile phenotype. Neointimal hyperplasia refers to post-intervention, pathological, vascular remodeling due to proliferation and migration of vascular smooth muscle cells in 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.  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.
Vascular wall injury may be due to manipulation by any of following procedures:
The events leading to neointimal hyperplasia can be broadly classified into the following:
Primary pathology is proliferation and migration of smooth muscle cells (SMCs) in tunica intima layer. Triggering step is endothelial damage or dysfunction (ED) due to vascular injury, which can occur secondary to vascular wall stretching during balloon angioplasty, vascular manipulation during carotid endarterectomy, or venous graft implantation during arteriovenous fistula formation or coronary bypass grafting.  ED leads to endothelial activation and decreases the production of nitrous oxide (NO) due to dysregulation of endothelial nitric oxide synthase (ENOS).  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 expression of endothelial adhesion molecules, such as vascular cell adhesion molecules, that helps recruitment and migration of monocytes into the subendothelial area. 
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. It is also noted in arteriovenous grafts studies that SMCs can alternately originate from fibroblasts from vascular adventitia or bone marrow progenitor cells.  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 expansion of the intimal layer and loss of luminal area.  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. 
Neointimal hyperplasia may be associated with recurrence of symptoms such as.
Workup should include the following:
Pharmacotherapy targeted at different steps of the pathogenesis of neointimal hyperplasia can be used to prevent and treat neointimal hyperplasia. Graft surveillance in high-risk patients with serial Doppler ultrasound within the first 2 years after the vascular intervention can early detect and repair neointimal hyperplasia. 
The following conditions can present similarly and need to be considered along with neointimal hyperplasia.
Depending on the organ system involved, vascular insufficiency can lead to the following:
Multidisciplinary team consultation may be required with the following:
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