VASCULAR FUNCTIONS OF NEUTROPHINS

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Preliminary results demonstrate that subpopulations of vascular smooth muscle cells express receptors for the NGF family of growth factors (neurotrophins). Neurotrophins are produced by smooth muscle cells, by blood platelets, and by the sympathetic neurons which innervate the vasculature. The functional role of neurotrophins in vascular development and response to injury will be examined. In situ hybridization and immunohistochemical techniques will be employed to characterize the pattern of expression of neurotrophins (NGF, BDNF, NT-3, NT-4) in developing mice. The effects of neurotrophins on cultured vascular smooth muscle cells will be examined. The capacity of cultured rat sympathetic neurons to transport neurotrophins down axons will be assessed. Functions of neurotrophins in vivo will be assessed by generating transgenic mice in which chimeric genes consisting of the dopamine beta-hydroxylase promoter upstream of coding sequences for BDNF and NT-3 cause enhanced expression of these factors in sympathetic neurons. The effects of blocking neurotrophin action on vascular smooth muscle cells in vivo will be assessed. This will be accomplished by generating transgenic mice in which neurotrophin receptor mutants with dominant negative action are expressed in smooth muscle cells under control of the promoter region of the hNGFR gene and/or the smooth muscle alpha actin gene.