Inhibition of Thrombin Receptor Signaling on alpha-Smooth Muscle Actin(+) CD34(+) Progenitors Leads to Repair After Murine Immune Vascular Injury

Objective-The goal of this study was to use mice expressing human tissue factor pathway inhibitor (TFPI) on alpha-smooth muscle actin (alpha-SMA)(+) cells as recipients of allogeneic aortas to gain insights into the cellular mechanisms of intimal hyperplasia (IH).

Methods and Results-BALB/c aortas (H-2d) transplanted into alpha-TFPI-transgenic (Tg) mice (H-2(b)) regenerated a quiescent endothelium in contrast to progressive IH seen in C57BL/6 wild-type (WT) mice even though both developed aggressive anti-H-2(d) alloresponses, indicating similar vascular injuries. Adoptively transferred Tg CD34(+) (but not CD34(-)) cells inhibited IH in WT recipients, indicating the phenotype of alpha-TFPI-Tg mice was due to these cells. Compared with syngeneic controls, endogenous CD34(+) cells were mobilized in significant numbers after allogeneic transplantation, the majority showing sustained expression of tissue factor and protease-activated receptor-1 (PAR-1). In WT, most were CD45(+) myeloid progenitors coexpressing CD31, vascular endothelial growth factor receptor-2 and E-selectin; 10% of these cells coexpressed alpha-SMA and were recruited to the neointima. In contrast, the alpha-SMA(+) human TFPI+ CD34(+) cells recruited in Tg recipients were from a CD45(-) lineage. WT CD34(+) cells incubated with a PAR-1 antagonist or taken from PAR-1-deficient mice inhibited IH as Tg cells did.

Conclusion-Specific inhibition of thrombin generation or PAR-1 signaling on alpha-SMA(+) CD34(+) cells inhibits IH and promotes regenerative repair despite ongoing immune-mediated damage.