Date of Award

4-2005

Degree Name

Doctor of Philosophy

Department

Biological Sciences

Abstract

Neurotrophic factors are important for neuronal growth, survival, and maintenance of cell phenotype. Glial cell line-derived neurotrophic factor (GDNF) affects sensory, autonomic and somatic motor neurons and nerve growth factor (NGF) affects sensory and sympathetic neurons. NGF and GDNF are produced by cardiac muscle and have potent effects on sensory and autonomic neuronal innervation of blood vessels. Neural innervation plays a key role in blood vessel function. Since neural innervation of blood vessels may be regulated by growth factors, we wanted to determine what changes would occur to NGF and GDNF levels with maturity, exercise and hypertension.

Changes in GDNF and NGF expression and innervation were examined in mesenteric vessels, hearts and in two models of hypertension, Dahl salt sensitive and Fischer 344 rats (L-NAME). Protein levels were examined using enzyme linked immunosorbant assay. Innervation density was studied using immunohistochemical methods. Increased pressure changes were examined using isolated cannulated vessel experiments.

GDNF levels were significantly higher in mesenteric veins versus mesenteric arteries. NGF levels were significantly higher in vessels of younger animals versus older animals. The localization of NGF and GDNF in blood vessels in sedentary animals was with fibers staining positive for tyrosine hydroxylase, indicating sympathetic innervation. In young or exercised animals NGF and GDNF were colocalized with calcitonin gene related peptide, indicating sensory innervation. Blood pressure also decreased with exercise.

Exercise had little effect on the NGF protein content in atria or ventricle but led to an increase in GDNF content in the left and right atria and ventricles. Activity dependent regulation of trophic factor in the heart may play a role in altered nerve structure and function observed following exercise training.

Finally, GDNF expression changed with the development of hypertension. In both models of in vivo hypertension, GDNF protein content increased in the vessels of hypertensive animals. In in vitro studies, 4 hours of elevated pressure increased the GDNF protein content above controls.

These data suggest that both NGF and GDNF may be regulated in an exercise dependent manner, change with maturity, and may be a factor in thedevelopment or maintenance of hypertension.

Access Setting

Dissertation-Open Access

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