Structural alterations of blood vessels play an important role in the adaptive response to physiologic stimuli and the pathologic development of vascular disease. Structural changes are dependent on the active process of vascular remodeling. Our broad definition of remodeling is a change in shape or geometry of the blood vessel mediated by a fundamental alteration in the structure. This structural alteration may (but no invariably) include changes in cell size or number and in extracellular matrix. The spectrum of vascular remodeling includes changes in the structural caliber of blood vessels in response to alterations in flow (flow induced vascular remodeling) and in response to luminal occlusion or narrowing due to pathologic proliferation of intimal cells (intimal hyperplasia in response to injury). Multiple steps are involved in the initiation of progression of vascular remodeling. Initially, a stimulus (hemodynamic or humoral factor) is sensed by the blood vessel thereby initiating the cascade of events which leads to structural changes. The hemodynamic stimulus may involve either changes in flow/shear stress or in pressure/stretch. Humoral and circulating factors such as lipoproteins, immune complexes, endotoxin, and vasoactive substances (such as angiotensin II) activate vascular sensors (receptors, ion channels, or part of the cytoskeleton) which transduce the signals to the cells of the blood vessel, frequently resulting in the expression of effector substances that subsequently mediate vascular remodeling. These effector substances include growth factors, cytokines, vasoactive substances, proteases, extracellular matrix components, and molecules which mediate cell-cell communication. The subsequent remodeling of the blood vessel involves the processes of cell growth, migration, and matrix modulation. This program project will address many of these issues in a systematic and coordinated fashion. The central theme of this project is the mechanism of vascular remodeling from the molecular to the in vivo level. Accordingly, our application consists of the following components: 1) mechanism of sensing and transducing circulating humoral and hemodynamic signals; 2) expression and synthesis of effector molecules mediating vascular remodeling; and 3) physiologic and pathologic models of vascular remodeling in animals and humans. The program project brings together investigators with multiple expertise ranging from molecular and cellular biology to biochemistry and from physiology to clinical investigation. This multidisciplinary, integrated approach allows us to address critical questions in the basic mechanisms of the remodeling process and its clinical significance in health and disease. The eight projects in this proposal address various aspects of the three major areas of concentration.
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