Inhibition of Thrombin Receptor Signaling on α-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 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-2d) transplanted into α-tissue factor pathway inhibitor–transgenic (Tg) mice (H-2b) regenerated a quiescent endothelium in contrast to progressive IH seen in C57BL/6 wild-type (WT) mice even though both developed aggressive anti-H-2d alloresponses, indicating similar vascular injuries. Adoptively transferred Tg CD34+ (but not CD34−) cells inhibited IH in WT recipients, indicating the phenotype of α-tissue factor pathway inhibitor–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 tissue factor pathway inhibitor+ 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.
- Received May 12, 2011.
- Accepted October 7, 2011.
- © 2011 American Heart Association, Inc.