Atherosclerosis and its associated complications are the leading cause of death in the United States. Atherosclerosis results from inflammation followed by dysregulation of arterial homeostasis that hinges on the balance between arterial injury and arterial repair. Arterial injury induced by risk factors such as hypertension, hyperlipidemia, smoking and aging results in vascular inflammation and endothelial cell (EC) senescence. During inflammation, activated endothelium produces pro-inflammatory cytokines/chemokines and cell adhesion molecules that recruit circulating leukocytes to the developing arterial plaque. Meanwhile, 'repair cells' are recruited to areas of injury and stave of the development of atherosclerosis. The main action of these repair cells may replace the injured EC and/or secrete paracrine factors. When successful, these reparative processes halt the inflammatory process, preventing further damage. However, chronic arterial injury may overwhelm the ability of repair cells to maintain arterial homeostasis. Thus, atherosclerotic lesions likely begin to form as arterial repair fails, rather than merely following arterial injury Although the specific cell types that repair the arterial wall have not yet been defined, experimental data from human patients suggests that Lin- bone marrow-derived cells (Lin- BMC) may be important for repair. We herein refer to these cells as repair competent bone marrow cells (RC- BMC). We have recently found that Notch signaling activity is differentially regulated in the EC lining the arterial plaque (in which a higher Notch activity is connected wit vascular inflammation and EC senescence). We also found that bone marrow progenitor/stem cells show progressively lower Notch activity as the arterial plaques progress. We hypothesize that alteration of Notch signaling regulates development/progression of atherosclerosis and modulates function of putative RC-BMC thus altering their ability to maintain arterial homeostasis. Our specific working hypothesis is that there exists a functional or causal relationship between high activity of Notch signaling and increasing atherosclerosis burden. Our testable 'proof-of-principle' hypothesis is that Notch signaling determines phenotype associated with arterial damage as well as repair capacity of BMC (RC Vs. RI). We propose to delineate the functional impact of Notch signaling on atherosclerosis development/progression and of alteration of Notch signaling activity (in Lin- BMC) on atherosclerosis plaque burden and plaque repair after disruption. We will also develop a clinically-relevant method for atherosclerotic lesion-specific cell delivery via an innovative nanoparticle-mediated technology. This work will exponentially advance knowledge on the pathogenesis of atherosclerosis and the role of progenitor/stem-cell-mediated arterial repair. Ultimately, the research may result in a paradigm-shifting therapeutic approach to the prevention and treatment of atherosclerosis.
Atherosclerosis results from inflammation followed by an imbalance between arterial damage and repair. Characterization of the signaling pathways (e.g. Notch signaling) determining endothelial cell phenotype associated with arterial damage and governing the repair capacity of repair competent bone marrow cells (RC- BMC) versus repair incompetent bone marrow cells (RI-BMC) will allow for the development of novel approaches to reduce arterial plaque and represent a significant and novel advancement in this arena of research.
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