The infusion of nerve growth factor (NGF) into the lateral ventricle of the mature rat brain elicits a sprouting response from axons associated with the intradural segment of the internal carotid artery. Using electron microscopic techniques, we observed a three-fold increase in the total number of perivascular axons. This NGF-elicited response is characterized by a dramatic reduction in glial cell ensheathment similar to that observed during development and by the presence of profiles devoid of organelles that may represent newly formed sprouts. In spite of the increase in axon number, no significant changes in the percentage of small, medium, or large axons were observed. The three-fold increase in the total number of axons was accompanied by an increase in the number of axons/fascicle but no change in the number of fascicles. This, along with the observation that a majority of sprouted axons were associated with other axons, supports the idea that the sprouted axons tend to associate preferentially with other axons. Bilateral superior cervical ganglionectomies following cytochrome C infusion indicate that approximately 60% of the axons associated with the internal carotid artery arise from the superior cervical ganglion and that the majority of axons contacting the smooth muscle layer arise from this ganglion. Sympathectomy following NGF infusion resulted in a 79% reduction in the total number of perivascular axons, demonstrating overwhelmingly that the majority of sprouted axons are sympathetic fibers. These results demonstrate that infusion of NGF into the mature rat brain results in the preferential sprouting of sympathetic axons associated with the internal carotid artery. These findings are consistent with the hypothesis that NGF normally plays a role in the regulation of autonomic cerebrovascular innervation in the adult animal and that mature, uninjured sympathetic neurons remain responsive to NGF.
Nerve growth factor (NGF) and neurotrophin-3 (NT-3) are target-derived proteins that regulate innervating sympathetic neurons. Here, we used western blot analysis to investigate changes in NGF and NT-3 protein in several peripheral tissues following loss of sympathetic input. Following removal of the superior cervical ganglion (SCG), large molecular weight (MW) NGF species, including proNGF-A, were increased in distal intracranial SCG targets, such as pineal gland and extracerebral blood vessels (bv). Mature NGF was a minor species in these tissues and unchanged following sympathectomy. Large MW NGF species also were increased when sympathectomy was followed by in vivo NGF administration. Mature NT-3, which was abundant in controls, was significantly decreased in these targets following sympathetic denervation. The decrease in mature NT-3 was enhanced following NGF administration. The trigeminal ganglion, which provides sensory input to these targets, showed increased NGF, but decreased NT-3, in these treatments, demonstrating that decreased NT-3 at the targets did not result from enhanced NT-3 uptake. Unlike pineal gland and extracerebral bv, the external carotid artery, an extracranial proximal SCG target, showed no change in NGF following denervation, and mature NT-3 was significantly increased. Following NGF administration, NT-3 was significantly decreased. We provide evidence for sympathetic regulation of NGF and NT-3 in peripheral targets and that elevated NGF can depress NT-3. The differential response in distal and proximal adult targets is consistent with the idea that neurons innervating proximal and distal targets may serve different roles in regulating neurotrophin protein. In addition, we conclude that previous ELISA results showing increased NGF protein following sympathetic denervation may have resulted from increases in large MW species, rather than an increase in mature NGF.
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