Blood vessel adaptation plays a central role in vascular biology because it represents an essential mechanism enabling normal tissue adaptation in chronic exercise and wound healing, as well as compensation for myocardial infarction, stroke, and trauma. Pathological vascular remodeling occurs in atherosclerosis, diabetes, and tumor growth. Microvascular adaptation plays an important role in overall cardiovascular homeostasis because the arterioles are a major determinant of total peripheral resistance and local blood flow distribution. Despite the importance of arterioles in vascular adaptation, virtually nothing is known regarding the origin of new arterioles in mature tissues, or the mechanisms governing their growth. This study is designed to test the central hypothesis that new arteriolar growth is initiated at existing precapillary arterioles, and that arteriolar network structure is primarily determined by vascular smooth muscle proliferation and differentiation mediated by the circumferential wall stress distribution. The long-range goal is to advance understanding of the cellular mechanisms responsible for microvascular remodeling in vivo.
The specific aims of the research are to determine the sites of new arteriole origin in vivo, the dependence of arteriolar remodeling on hemodynamic stresses, and the rate of arteriolar growth in a chronic model of elevated circumferential wall stress. A whole mount delivery technique will be used to perform triple antibody labeling of vascular smooth muscle (VSM) alpha-actin and myosin heavy chain contractile proteins, and bromodeoxyuridine (BrDU) uptake, in intact vascular networks, allowing immunocytochemical characterization of VSM phenotype and growth state to distinguish cells involved in proliferation, immature cells, and differentiated cells. This new method allowing visualization of arteriolar growth sites in vivo will be used to examine growth during l) acute vasodilation of rat gracilis muscle microvasculature, 2) controlled perfusion of gracilis muscle, in conjunction with direct measurement of arteriolar pressure, flow, and dimensions, to achieve acute, independent changes in vessel wall shear stress and circumferential wall stress, and 3) chronic ligation of arterial supply for study of long-term network adaptation to non-uniform wall stresses. Together these experiments will allow a test of the hypothesis that circumferentiaI wall stress is a significant determinant of microvascular remodeling during normal adaptation in skeletal muscle, and that pre-capillary arterioles are the origin of new arterioles formed by VSM proliferation or differentiation Finally, using a hemodynamic computer network model to link the measured arteriolar growth to the distribution of hemodynamic stress, a test will be made of the hypothesis that the macroscopic network remodeling over the long-term is quantitatively related to the underlying VSM proliferative and differentiation response at the cellular level. The capability to link cellular or microcirculatory events to macroscopic organ hemodynamics provides a basis for understanding the relative roles of hemodynamic stresses and extravascular production of mitogens in vascular adaptation, leading ultimately to improved therapeutic measures.
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