Cerebral arterial innervation: II. Development of calcitonin-gene-related peptide and norepinephrine in the rat

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Abstract
The pre- and postnatal development of trigeminal calcitonin-gene-related peptide (CGRP)- and sympathetic norepinephrine (NE)-containing nerves supplying the cerebral arteries was studied with immunohistochemistry in rats. At 18–19 days in utero (E 18–19), CGRP fibers were present only as one or two longitudinal bundles zigzagging along the anterior cerebral artery and anterior communicating artery. Growth-cone-like swellings were found at the terminals of individual fibers. In contrast, at this same prenatal age NE fibers were present as a meshwork on all cerebral arteries. The density of NE fibers was higher in the rostral than in the caudal parts of the circle of Willis; growth cones were present on individual fibers at the middle segment of the basilar artery and distal parts of major cerebral arteries. At postnatal day 1–2 (PND 1–2; date of birth = PND 1), the outgrowth of CGRP axons extended along the walls of the middle cerebral and internal carotid arteries. These axons were relatively straight and unbranched. At the same time, NE fibers increased in number and density and continued to form the meshwork pattern on all cerebral arteries. At the end of the first postnatal week, all the longitudinal NE bundles on the rostral part of the circle of Willis began to form circular arborizations. At the end of the second postnatal week, the pattern of NE innervation had completely changed, consisting almost entirely of circumferential rather than tangential fibers. Beginning in the first postnatal week, CGRP fibers increased greatly in number and density and began to form a meshwork pattern. At the second postnatal week, the pattern of CGRP innervation, compared to the pattern at fetal and neonatal stages, had changed significantly, consisting predominantly of a meshwork pattern. By 4 weeks after birth, both the NE and CGRP fiber systems achieved adult densities and patterns. The present results demonstrate the following: (1) Both sympathetic-NE and trigeminal-CGRP innervation of cerebral arteries begin in utero; the NE system innervates corresponding parts of the vessels earlier than the CGRP system. (2) Both NE and CGRP fibers are more dense in the rostral than in the caudal segments of the circle of Willis; this rostrocaudal gradient is expressed in both density and pattern by the earliest fibers of both neurochemical systems and is maintained throughout all developmental stages. (3) The mature pattern of trigeminal CGRP fibers is a meshwork; the mature pattern of the sympathetic NE fibers is circumferential; both of these fiber systems undergo developmental reorganization to achieve adult innervation patterns in the second postnatal week. At this point in time, NE fibers rapidly transform from a meshwork pattern, similar to the mature pattern of trigeminal CGRP fibers, to an entirely circumferential pattern in only 1 week. The events which regulate this dramatic transformation are unknown. As there are no abrupt changes in vessel diameter during this period, mechanical factors probably do not play a decisive role. Factors which may be important include the central innervation of ganglionic neurons, competition for vascular synaptic sites, neurotrophic signals, or modifications in the structure of the vascular wall.