Inhibition of thrombin receptor signaling on α-smooth muscle actin + CD34 + progenitors leads to repair after murine immune vascular injury

Abstract

Objective-: The goal of this study was to use mice expressing human tissue factor pathway inhibitor (TFPI) on α-smooth muscle actin (α-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-2 d) transplanted into α-TFPI- transgenic (Tg) mice (H-2 d) 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 α-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 α-SMA and were recruited to the neointima. In contrast, the α-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 α-SMA + CD34 + cells inhibits IH and promotes regenerative repair despite ongoing immune-mediated damage. © 2011 American Heart Association, Inc.