Molecular evidence for arterial repair in atherosclerosis

Abstract

Atherosclerosis is a chronic inflammatory process and progresses through characteristic morphologic stages. We have shown previously that chronically injecting bone-marrow-derived vascular progenitor cells can effect arterial repair. This repair capacity depends on the age of the injected marrow cells, suggesting a progressive decline in progenitor cell function. We hypothesized that the progression of atherosclerosis coincides with the deteriorating repair capacity of the bone marrow. Here, we ascribe patterns of gene expression that accurately and reproducibly identify specific disease states in murine atherosclerosis. We then use these expression patterns to determine the point in the disease process at which the repair of arteries by competent bone marrow cells ceases to be efficient. We show that the loss of the molecular signature for competent repair is concurrent with the initiation of atherosclerotic lesions. This work provides a previously unreported comprehensive molecular data set using broad-based analysis that links the loss of successful repair with the progression of a chronic illness.genomic ͉ vascular progenitor cell ͉ aging ͉ inflammation ͉ bone marrow obsolescence

Jay and Jeanie Schottenstein Prize in Cardiovascular Science: Predicting Cardiovascular Illnesses for the 21st Century, and the Unpredictable …

“…We also were able to define a molecular signature that corresponds to efficient repair of the arterial wall (11). Genes that constitute this pool often have to do with cellular functions that are important for stem cells.…”

“…However, a couple of years ago, we showed for the first time that atherosclerosis is not simply the result of direct injury to the arterial wall, but instead the consequence of such injury in a context in which the intrinsic repair process for the arterial wall is no longer fully functional (6,7). Our laboratory (11) and other groups of investigators (5) have shown that arterial repair is triggered by arterial injury, which, in turn, provokes a local inflammatory reaction (7) (Fig. 1).…”

“…There, they may contribute to regenerating a functional endothelium through cell growth, differentiation, and many other activities that include paracrine functions (3). We have shown that mice that are exposed to proatherosclerotic factors, such as a high lipid content of the blood, lose over time their capacity to mount a functional repair activity (11,17) (Fig. 3).…”

“…With an apolipoprotein E (ApoE) knockout model on a high-fat diet in which mice rapidly develop lesions rather typical of human atherosclerosis (total cholesterol usually exceeds 1,000 mg/dl), we have characterized the molecular signature for various stages of the progression of atherosclerosis. Through the identification of genes whose expression is pathognomonic for each stage of the disease, we reconstituted the molecular puzzle of atherosclerosis progression (11) (Fig. 3).…”

“…By using gene-expression analysis, we have reconstituted the natural history of atherosclerosis by analyzing changes in gene expression that are associated with successive stages of the atherosclerotic process (11) (Fig. 3).…”