Although collateral dilation and development are essential processes to limit the severity of arterial occlusive diseases, the limited information available for collateral reactivity is contradictory and the primary mechanisms responsible for collateral development remain controversial. An in vivo model in which flow is increased without altering pressure in collateral arteries will be used to investigate the role of wall shear forces in chronic alterations of tone and reactivity as well as wall remodeling. Collateral arteries in this model undergo substantial luminal enlargement at sites shear stress is increased. During liminal enlargement, endothelial proliferation occurs within days after shear is elevated, followed by smooth muscle hyperplasia as shear is decreased and finally, cellular regression occurs after shear is normalized. Published and preliminary studies suggest that nitric oxide (NO) has a significant role I shear-mediated vascular remodeling and regulation of mature and immature collaterals. The role of both wall shear and NO in regulation the rate and nature of wall expansion will be investigated for both abrupt and gradual occlusion. Early, intermediate, and late stages of development will be evaluated the role of the NO system will be evaluated by measurement of NO concentration with microelectrodes, quantitation of NO synthase mRNA and protein levels with in situ hybridization and immunohistochemistry, and inhibition of NO synthase. Active and passive regulation of arterial diameter will be investigated with in vivo techniques to determine the extent to which abnormalities are due to elevated shear rate or wall remodeling. Active tension generation by smooth muscle cells, endothelial adaptations, and passive distensibility will all be assessed the results of the proposed experiments should clarify the roles of wall shear forces and NO in collateral development, and establish the basis for enhancement or suppression of collateral vasoregulation. The studies are of clinical significance as most of the risk factors for vascular diseases are associated with impaired NO mechanisms, which are anticipated to be very important in both collateral development and reactivity. Furthermore, the results may establish the basis for differences in responses to abrupt versus gradual occlusion.
