Pathogenetic mechanisms of cardiac allograft vasculopathy - impact of nitric oxide

In the cytokine-enriched environment of the chronically rejecting allograft , nitric oxide (NO) is predominantly produced by the inducible isoform of N OS synthase (NOS2) expressed by recipient-derived infiltrating immune cells as well as donor-derived vascular smooth muscle cells and endothelial cell s. Early and persistent upregulation of NOS2 in allografts with cardiac all ograft vasculopathy and downregulation of NOS2 coinciding with immunosuppre ssive attenuation of cardiac allograft vasculopathy have suggested NO as a regulator of cardiac allograft vasculopathy, the hallmark of chronic reject ion. Pathogenetically, the development of cardiac allograft vasculopathy can be divided into an early phase, characterized by endothelial dysfunction, and a later phase, characterized by structural changes of vessel wall morpholog y. Several lines of evidence have shown that NO might play an essential rol e in both phases. Endothelial dysfunction due to immune-mediated injury of endothelial cells has been suggested as an early response-to-injury event in the pathogenesis of cardiac allograft vasculopathy. Functional studies in human transplant recipients have documented endothelial dysfunction of coronary artery vesse ls. Administration of L-arginine, the precursor of NO, improved endothelial function of both epicardial coronary arteries and coronary microvasculatur e indicating a protective effect of NO. To assess the impact of NO on the development of late structural changes, t he severity of cardiac allograft vasculopathy was assessed in mice with tar geted deletion of NOS2. A significant increase of vascular occlusion in NOS 2-knockout mice demonstrated an antiarteriosclerotic effect of NOS2. In par t, this effect could be explained by reduced neointimal smooch muscle cell accumulation after alloimmune injury. Taken together, NO plays an important role in maintaining vessel integrity after transplantation Disruptions in NO pathways seem to play a key role in the progression from endothelial dysfunction to structural changes.