Bolus Delivery of Mesenchymal Stem Cells to Injured Vasculature in the Rabbit Carotid Artery Produces a Dysfunctional Endothelium

Endothelial dysfunction is an important factor in cardiovascular pathology. It has been suggested that pluripotent mesenchymal stem cells (MSCs) may contribute to repair of the endothelium through paracrine pathways. Enhanced re-endothelialization may be associated with a better outcome following angioplasty procedures. We examined the effect of the delivery of MSCs to a denuded vessel in vivo. The right carotid arteries of New Zealand white rabbits were denuded using an uninflated 3-French Fogarty balloon catheter. 1 x 10(5) MSCs in a bolus of 150 microL were then delivered intraluminally and allowed to dwell for 20 min. MSC engraftment was assessed using PKH-26 labeling and transduction with adenoviral reporter genes. Vessels were examined at 2 weeks for levels of endothelialization, as well as for neointimal hyperplasia and vasomotor function. Engraftment of MSCs was noted in the vessel wall following local arterial delivery. Endothelialization was improved following bolus MSC delivery at 2 weeks post-intervention. However, this endothelium is manifestly dysfunctional as indicated by a significant impairment in vasomotor activity and a significant increase in neointimal formation post-bolus delivery. Consistent with the formation of a dysfunctional endothelium, there was a higher rate of vessel occlusions in bolus-treated vessels due to not only predominately thrombosis but also neointimal hyperplasia. Our results suggest that naive MSCs delivered as a bolus to the occluded injured vascular segment generate dysfunctional endothelium presenting a risk of vessel occlusion. Such risks are important and need to be further assessed.