Grant: Operating Grant

Hardening of the arteries occurs in blood vessels of one's own heart and those that have been transplanted, in people throughout Canada and worldwide. The nature of this hardening is distinct and more accelerated than that which occurs in our own hearts. The reasons why this devastating condition occurs in transplanted hearts, often leading to silent heart attacks and death of the organ recipient, are unknown. We do know that the immune system of the recipient responds against the transplanted heart, but we do not know how the vessels in the heart are injured nor how they become narrowed. Endothelial cells (EC) line the inner surface of the blood vessels, separating the vessel wall from the bloodstream, and when injured early post-transplantation, lead to many adverse consequences, including artery narrowing. Substances responsible for injury and subsequent poor function of EC are only partially known. Among factors of interest in this regard, Vascular Endothelial Growth Factor (VEGF) on one hand causes EC renewal or healing, as well as the recruitment of stem cells which may help heal the endothelium, and on the other hand, appear to diminish EC integrity. VEGF is increased in availability in artery walls of transplanted hearts, and when present in excess, as it is in this disease, may be adverse to arterial health. We will define in detail how the integrity of the endothelium is modified by VEGF and how this factor works to do so. As well, we will identify the role of the recipient's bone marrow, and how it may repair and replace damaged EC. This work will be accomplished using state-of-the-art technology and cell culture models using human EC. As well, we will examine the degree and contribution of bone marrow-derived stem cells in our mouse model of heart transplantation. The results from this study will provide unique insight into the beneficial and detrimental roles of VEGF, and allow for the use of specific therapies at specific times to address these.