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 (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).


RESULTS
BALB/c aortas (H-2(d)) transplanted into α-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 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.


CONCLUSIONS
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.
Medical Research Council Centre for Transplantation, King's College London, Guy's Hospital, London SE1 9RT, United Kingdom.
Daxin
D
Chen
Seema
S
Shrivastava
Liang
L
Ma
El-Li
el-L
Tham
Joel
J
Abrahams
J David
JD
Coe
Diane
D
Scott
Robert I
RI
Lechler
John H
JH
McVey
Anthony
A
Dorling
D000199:Actins / Q000378:metabolism*; D019264:Adoptive Transfer; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001011:Aorta / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D020212:Carotid Artery Injuries / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032390:Myoblasts, Smooth Muscle / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058426:Neointima / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000235:genetics; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014945:Wound Healing / Q000502:physiology; D010975:Platelet Aggregation Inhibitors
D000199:Actins; D018952:Antigens, CD34; D008074:Lipoproteins; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; C544013:alpha-smooth muscle actin, mouse; C051928:lipoprotein-associated coagulation inhibitor; D010975:Platelet Aggregation Inhibitors