Regulation of human aortic endothelial cell-derived mesenchymal growth factors by allogeneic lymphocytes in vitro: A potential mechanism for cardiac allograft vasculopathy

Abstract

Cardiac allograft vasculopathy is thought to be triggered by an alloreactive response to the donor coronary vasculature, resulting in smooth muscle cell proliferation and ultimate occlusion of the donor coronary arteries. To determine whether allogeneic lymphocytes are capable of regulating endothelial-derived smooth muscle cell (SMC) growth factors, human aortic endothelial cells (HAECs ) were exposed to allogeneic lymphocytes. The HAEC-lymphocyte co-cultures were assessed for (a) lymphocyte proliferation in response to the allogeneic HAECs; (b) release of soluble factors that stimulate human aortic SMC proliferation; and (c) alteration of HAEC mRNA levels for a panel of known SMC growth factors. Co-culture conditioned medium increased SMC proliferation, compared to medium conditioned by HAECs alone. HAECs exposed to allogeneic lymphocytes increased their expression of mRNA for basic fibroblast growth factor, transforming growth factors α and β, and platelet derived growth factor A and B chains. These results demonstrate that allogeneic lymphocytes are capable of inducing HAECs to increase mRNA levels for several mesenchymal growth factors and to release bioactive products capable of stimulating SMC cell proliferation in vitro. Additionally, the data support the hypothesis that alloreactive lymphocytes can stimulate allogeneic donor endothelial cells to produce growth factors that may contribute to the intimai thickening seen in cardiac allograft vasculopathy.