Changing paradigm for neointimal cell origin: Is restenosis a blood‐borne disease?

The principal mechanism of restenosis in coronary balloon angioplasty without stenting is negative, constrictive vascular remodeling. Stent implantation overcomes this problem, but creates in-stent restenosis (ISR) from thick neointima as a new iatrogenic limitation to coronary stenting. Drug-eluting stents (DESs) effectively limit ISR but have not solved it completely [1]. Rapamycin and paclitaxel elution from stents have many effects, including antiproliferative, antimigratory, and antisecretory components. Differentiating which of these are most important is not yet possible and remains a challenge for research in modern vascular biology. Neointimal tissue is the principal cause of ISR [2] and is caused by smooth cells in early stages that later secrete extracellular matrix [3,4]. While DESs have made great clinical strides against neointima, the mechanisms of ISR are not fully understood. Understanding these mechanisms will improve methods for its limitation. Traditional concepts of vascular reaction after coronary stenting entail thrombus formation, cell proliferation, migration, and endothelialization [5]. In the past several years, investigators seeking to understand cell proliferation discovered several mitogenic signals for these cells. These include the ras-raf-mitogen-activated protein kinases (MAPK) pathway and cyclic adenosine monophosphate (cAMP)-dependent signaling [6]. Multiple experimental and clinical studies demonstrate that alterations in the balance of growth components in the vessel wall influence cell growth, survival, migration, and extracellular matrix synthesis, in turn modulating neointimal formation [7].