Systemic application of sirolimus prevents neointima formation not via a direct anti-proliferative effect but via its anti-inflammatory properties.

BACKGROUND: Systemic treatment with sirolimus, as used for immunosuppression in transplant patients, results in markedly low rates of in-stent restenosis. Since the underlying mechanisms remain obscure, we aimed to determine the molecular and cellular effects of systemic sirolimus treatment on vascular remodeling processes. METHODS AND RESULTS: Systemic sirolimus treatment significantly reduced smooth muscle cell (SMC) proliferation 14days after wire-induced injury and neointima formation 28days after injury in C57BL/6 mice, while simultaneously impairing re-endothelialization. Interestingly, in vitro, sirolimus had no direct effect on the proliferation of SMC or endothelial cells (EC) at serum concentrations observed after systemic application. In contrast, sirolimus reduced the adhesion of leukocytes (CD45+) and bone marrow-derived progenitor cells (CD34+) to activated EC by down-regulating the adhesion molecules ICAM-1 and VCAM-1. In addition, sirolimus treatment also significantly reduced the upregulation of ICAM-1 and VCAM-1 and the recruitment of monocytic cells (MOMA-2+) in neointimal lesions in vivo. CONCLUSION: Our findings show that systemic sirolimus treatment effectively prevents SMC and EC proliferation in vivo without directly affecting these cells. Instead, sirolimus prevents neointima formation and re-endothelialization by attenuating the inflammatory response after injury with secondary effects on SMC and EC proliferation. Thus, despite a similar net effect, the mechanisms of systemic sirolimus treatment are largely different from the local effects achieved after application of sirolimus-eluting stents.

The G534E polymorphism of the gene encoding the factor VII-activating protease is associated with cardiovascular risk due to increased neointima formation.

The G534E polymorphism (Marburg I [MI]) of factor VII-activating protease (FSAP) is associated with carotid stenosis and cardiovascular disease. We have previously demonstrated that FSAP is present in atherosclerotic plaques and it is a potent inhibitor of vascular smooth muscle proliferation and migration in vitro. The effect of wild-type (WT)- and MI-FSAP on neointima formation in the mouse femoral artery after wire-induced injury was investigated. Local application of WT-FSAP led to a 70% reduction in the neointima formation, and this effect was dependent on the protease activity of FSAP. MI-FSAP did not inhibit neointima formation in vivo. This is due to a reduced proteolytic activity of MI-FSAP, compared to WT-FSAP, toward platelet-derived growth factor BB, a key mediator of neointima development. The inability of MI-FSAP to inhibit vascular smooth muscle accumulation explains the observed linkage between the MI-polymorphism and increased cardiovascular risk. Hence, FSAP has a protective function in the vasculature, and analysis of MI polymorphism is likely to be clinically relevant in restenosis.