Submitted October 26, 2007
Accepted February 1, 2008
Regenerative repair after endoluminal injury in mice with specific antagonism of protease activated receptors on CD34+ vascular progenitors
Daxin Chen, Joel M Abrahams, Leanne M Smith, John H. McVey, Robert I Lechler, and Anthony Dorling*
Department of Immunology, Imperial College London, Hammersmith Hospital, London, United Kingdom
Haemostasis and Thrombosis Unit, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, United Kingdom
* Corresponding author; email: a.dorling{at}imperial.ac.uk.
Tissue factor (TF) and thrombin are involved in intimal hyperplasia (IH) and remodelling following vascular injury. Because many neointimal smooth muscle cells (VSMC) derive from circulating vascular progenitors (VPs), we investigated how thrombin influences VP phenotype and function. Following wire-induced carotid artery injury in mice, the majority of circulating VP expressed TF, were capable of initiating clotting in vitro, and had protease activated receptors (PAR)-1, 2 and 4. Thrombin, through PAR-1, inhibited apoptosis and caused proliferation resulting in the outgrowth of VP co-expressing markers of activated endothelial cells and VSMC, even in the presence of growth factors. These mixed phenotype VP circulated as a minority population after injury and shared a similar phenotype with many neointimal cells. Labelled CD34+ cells, injected up to two weeks post-injury could be detected in the injured vessel wall, suggesting that continued recruitment may contribute to progressive IH. Finally, CD34+ cells incubated with thrombin prior to injection promoted florid neointimal lesions, whereas those incubated with PAR antagonists inhibited IH and promoted regenerative repair characterised by the development of a quiescent endothelium. We conclude that IH post-vascular injury is due to the direct actions of thrombin on mobilised VPs.
