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

Arterioscler Thromb Vasc Biol. 2012 Jan;32(1):42-9. doi: 10.1161/ATVBAHA.111.239046. Epub 2011 Oct 27.


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(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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism*
  • Adoptive Transfer
  • Animals
  • Antigens, CD34 / metabolism
  • Aorta / immunology
  • Aorta / metabolism
  • Aorta / pathology
  • Aorta / transplantation
  • Carotid Artery Injuries / immunology
  • Carotid Artery Injuries / metabolism*
  • Carotid Artery Injuries / pathology
  • Humans
  • Lipoproteins / genetics
  • Lipoproteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myoblasts, Smooth Muscle / immunology
  • Myoblasts, Smooth Muscle / metabolism*
  • Myoblasts, Smooth Muscle / pathology
  • Neointima / immunology
  • Neointima / metabolism
  • Neointima / pathology
  • Receptor, PAR-1 / antagonists & inhibitors
  • Receptor, PAR-1 / deficiency
  • Receptor, PAR-1 / genetics
  • Receptors, Thrombin / antagonists & inhibitors*
  • Receptors, Thrombin / metabolism
  • Signal Transduction
  • Wound Healing / physiology


  • Actins
  • Antigens, CD34
  • Lipoproteins
  • Receptor, PAR-1
  • Receptors, Thrombin
  • alpha-smooth muscle actin, mouse
  • lipoprotein-associated coagulation inhibitor