Project Examples Several examples of projects currently under investigation are detailed below: To understand what makes blood vessels grow where needed and how tissues "know" the number of vessels they require. This area includes studies of angiogenesis, vasculogenesis, collateral formation and vascular remodeling. Researchers use several strategies, including manipulation of genes that regulate vessel growth and blood flow in mouse models. Genetic approaches are being used to study the genes responsible for changes in blood vessel size. In particular, changes in blood flow are being used to alter vessel size and analyze the genes by crossing specific inbred mouse strains. Studies of how the vascular system develops and remodels in response to physiologic changes may allow us to control blood flow to tumors, or to circumvent blood clots by growing new vessels through a process called angiogenesis. Researchers study the role of reactive oxygen species to understand how a tissue deprived of oxygen, or exposed to oxygen after being deprived of it, incurs damage. Reactive oxygen species include superoxide, hydrogen peroxide and the hydroxyl radical. These molecules have pathophysiological actions in atherosclerosis as shown by the findings that oxidized low density lipoprotein (LDL) is more atherogenic than native LDL. Additionally, in hypertension there is increased generation of these species in blood vessels. Finally, generation of reactive oxygen species is a major cause of cell death in stroke and myocardial infarction. A key research area is to understand the molecular mechanisms by which the extracellular matrix controls cell behavior. Projects are focused on understanding how fibronectin and fibronectin polymerization regulate vascular cell proliferation and extracellular matrix remodeling events that play critical roles during angiogenesis and during the cell response to injury. The mechanisms of insulin resistance that contribute to the increase in cardiovascular mortality in diabetics are being studied both in blood vessels and in the heart. The focus is on a family of transcription factors termed peroxisome proliferator-activated receptors (PPARs) that are the targets for drugs like pioglitazone and rosiglitazone. The key signaling pathways involved in the development of transplant arteriopathy which is the leading cause of long term morbidity and mortality following heart transplantation remain undefined. Animal models have shown that there is an early inflammatory response to transplant characterized predominantly by macrophage and lymphocyte accumulation within the graft. Subsequently intimal proliferation develops- an accumulation of smooth muscle cells and inflammatory cells. Recent studies have suggested that some of these intimal cells may be bone marrow precursor cells. The focus of our current research is on the role of PPARs in the development of transplant arteriopathy. The mechanisms by which hemodynamic forces such as pressure, stretch and fluid shear stress are sensed by cells within the cardiovascular system are under investigation. Importantly these pathways contribute to the atheroprotective benefits of steady laminar blood flow. The changes in genetic program in hearts as they transition from normal to damaged to failing is being studied by animal models and microarrays. A number of novel genes that are associated with both the development and regression of cardiac disease have been identified using a large-scale gene expression profiling approach with both mouse and human heart tissue from non-failing, failing, and phenotypically"rescued" cardiac phenotypes. In collaboration with the Heart Research Follow-up Program (Drs. Couderc, Moss and Zareba) activities focus on the quantitative assessment of ventricular repolarization from the surface electrocardiograms (ECGs). Based on digital signal processing methods, we investigate both static and dynamic aspects of cardiac repolarization (morphology, heterogeneity, variability, and alternans). Investigations into the clinical features and genetic underpinnings of the inherited long QT syndrome, a channelopathy associated with arrhythmogenic syncope and sudden death in the young. The role of special inflammatory molecules termed chemokines in vascular inflammation is under investigation. In addition the link between inflammation and thrombosis is being studied focusing on the pro-coagulant protein tissue factor. The function of a family of proteins termed phosphodiesterases (PDEs) that degrade cyclic GMP and cyclic AMP is being studied for their potential roles in cardiovascular diseases such as hypertension, atherosclerosis, and heart failure. Drugs such as sildenafil (Viagra) that target PDEs represent an exciting new area of pharmaceutical development. Ongoing projects include studies of the role of PDE1A in the regulation of vascular contractility and growth; the role of cAMP PDEs in the regulation of vascular inflammatory responses and atherosclerosis; and the role of PDE3 in heart failure. The transcriptional program(s) of normal SMC differentiation are being studied. One project is to study the function of a novel retinoid-inducible tumor suppressor called AKAP12, a new protease called RISC, and an alpha integrin subunit. To test the hypothesis that SMC-restricted gene expression is mediated by modular elements residing remotely from the core promoter, BAC recombineering and transgenic mouse/fish models are used in conjunction with various bioinformatics tools to define regulatory elements governing SMC differentiation in vivo. Finally the roles that serum response factor and its coactivator myocardin in “turning-on” a program of SMC differentiation are being studied. The mechanisms by which exercise benefits cardiovascular health are being studied. Specifically inbred mouse strains are being compared to identify genes that confer greater responses to exercise training.