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Review
. 2010 Jul;22(7):639-49.
doi: 10.1111/j.1365-2826.2010.02033.x. Epub 2010 May 18.

Gonadotrophin-releasing Hormone Nerve Terminals, Tanycytes and Neurohaemal Junction Remodelling in the Adult Median Eminence: Functional Consequences for Reproduction and Dynamic Role of Vascular Endothelial Cells

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Review

Gonadotrophin-releasing Hormone Nerve Terminals, Tanycytes and Neurohaemal Junction Remodelling in the Adult Median Eminence: Functional Consequences for Reproduction and Dynamic Role of Vascular Endothelial Cells

V Prevot et al. J Neuroendocrinol. .
Free PMC article

Abstract

Although coordinated actions of several areas within the hypothalamus are involved in the secretion of gonadotrophin-releasing hormone (GnRH), the median eminence of the hypothalamus, where the nerve terminals are located, plays a particularly critical role in the release of GnRH. In adult females, prior to the preovulatory surge of GnRH, the retraction of specialised ependymoglial cells lining the floor of the third ventricle named tanycytes allows for the juxtaposition of GnRH nerve terminals with the adjacent pericapillary space of the pituitary portal vasculature, thus forming direct neurohaemal junctions. These morphological changes occur within a few hours and are reversible. Such remodelling may promote physiological conditions to enhance the central release of GnRH and potentiate oestrogen-activated GnRH release. This plasticity involves dynamic cell interactions that bring into play tanycytes, astrocytes, vascular endothelial cells and GnRH neurones themselves. The underlying signalling pathways responsible for these structural changes are comprised of highly diffusible gaseous molecules, such as endothelial nitric oxide, and paracrine communication processes involving receptors of the erbB tyrosine kinase family, transforming growth factor beta 1 and eicosanoids, such as prostaglandin E(2). Some of these molecules, as a result of their ability to diffuse within the median eminence, may also serve as synchronizing cues allowing for the occurrence of functionally meaningful episodes of GnRH secretion by coordinating GnRH release from the GnRH neuroendocrine terminals.

Figures

Figure 1
Figure 1
Schematic representation of the cell types (tanycytes, astrocytes and endothelial cells) and neuronal elements (neuroendocrine terminals) that reside within the median eminence of the hypothalamus. The median eminence of the hypothalamus is the brain structure forming the floor of the third ventricle (3V). The median eminence, which is one of the circumventricular organs of the brain is capable of conveying information from the brain to the periphery via the release of neurohormones into the circulation and, conversely sensing information reaching the brain via the bloodstream.
Figure 2
Figure 2
Electron micrographs illustrating the dynamic changes occurring in the external zone of the median eminence that control the direct access of GnRH nerve terminals to the pericapillary space during the reproductive cycle in the rat. Left panel, Electron micrograph of GnRH-immunoreactive terminals (large arrowhead) in the external zone of the median eminence in close proximity of the fenestrated capillaries (Cap) of the portal vasculature. At most stages of the reproductive cycle, GnRH nerve terminals (labeled with 15-nm gold particles) are entirely embedded in tanycytic endfeets (Tan), which prevent them from contacting the pericapillary space (p.s.) delineated by the parenchymatous basal lamina (arrow). Arrowhead, endothelial basal lamina; short arrows, fenestration of the endothelium. Scale bar: 0.5 mm. Right panels, On proestrus, the time of the occurrence of the preovulatory GnRH/LH surge, a significant fraction of GnRH nerve endings (large arrowhead) directly contact the pericapillary space (p.s.) either through filopodial extension of the nerve terminal (arrows) (Bottom right panel) or (Top right panel) by evaginations of the parenchymatous basal lamina (small black arrowheads) that allows the pericapillary space (p.s., asterisk) to penetrate into the nerve parenchyma. In the top right panel note the presence of numerous small clear synaptic vesicles (white vesicles of small size, white arrowhead) and the fusion of secretory granules (large-sized black vesicles) with the axo-plasmic membrane of the GnRH nerve terminal in direct apposition with the parenchymatous basal lamina (small arrows). The penetration of the pericapillary space into the nerve parenchyma on the day of proestrus may result from the morphological remodeling of tanycytic end-feets (tan) anchored to the parenchymatous basal lamina through hemidesmosomes seen as dark thickenings within the tanycytic processes in apposition with the basal lamina, small white arrowhead. Scale bar: 0.5 μm. From [10,11] with permission.
Figure 3
Figure 3
The COX product PGE2 causes cell retraction in tanycytes in vitro and promotes neuronal-glial plasticity in hypothalamic explants containing the median eminence, causing the advancement of GnRH neurosecretory terminals towards the pericapillary space. A, The addition of PGE2 (280 nM, 30 min), one of the most biologically active of COX products, caused acute tanycyte retraction. Tanycytes were stained with Alexa-conjugated phalloidin to visualize filamentous actin (red) and with Hoechst to stain nuclei (blue). Scale bar: 10 μm. B, Representative electron micrographs of GnRH immunoreactive axon terminals (15 nm gold particles; long black arrowhead) from female rat median eminence explants incubated for 30 min in the presence (PGE2) or in the absence (Control) of PGE2 (1 μM). Under basal unstimulated conditions, GnRH nerve endings (long black arrowhead) were maintained at a distance from the brain basal lamina (white arrow) delineating the pericapillary space (p.s.), by thick enclosing tanycyte end-feet (Tan.). PGE2 treatment caused the advancement of GnRH axon terminals (long arrowhead) toward the brain basal lamina (white arrow) and the apparent retraction of most of the astroglial sheath (black arrows) from those neurosecretory terminals that were separated from the fenestrated (small arrowhead) portal capillaries (cap.) by only a few nanometers. end., endothelium. Scale bar, 1 μm. From [43] with permission.
Figure 4
Figure 4
In the median eminence of the hypothalamus, endothelial nitric oxide (NO) secretion may represent one of the synchronizing cues that by coordinating GnRH release from GnRH neuroendocrine terminals that are distributed over 2 mm within the median eminence allows the occurrence of functionally meaningful episodes of GnRH secretion. (A) Real time amperometric measurement of spontaneous NO release from median eminence explants at different stages of the rat estrous cycle. DiII, diestrus II; PRO, proestrus; E, estrus. (B) On the afternoon of proestrus, the preovulatory GnRH/NO release is blocked with L-NIO, an NOS inhibitor selective for eNOS at 0.5 μM. * and a, significantly different from treated samples, p , 0:05: AUC: area under the curve during a 30 min period. (C) Photomicrograph showing GnRH axonal fibers in the external zone of the median eminence (green fluorescence, arrows) in close apposition to eNOS-immunoreactive portal vasculature (red fluorescence, arrowheads). 3V, third ventricle. The dotted lines outline the third ventricle. Scale bar: 75 μm. (A, B) Reproduced with permission from [76]; (C) reproduced with permission from [78].
Figure 5
Figure 5
Schematic representation of neural-glial-endothelial interactions involved in the control of GnRH neurosecretion in the median eminence. Glial-neuronal interactions in the median eminence involve the production of epidermal growth factor (EGF)-related peptides, TGFα and neuregulins (NRG), by tanycytes and astrocytes. The binding of TGFα to tanycytic and/or astrocytic erbB-1 receptors, as well as the binding of NRGs to astrocytic erbB-4 receptors results in the recruitment of erbB-2 co-receptors and signal transduction. The downstream signaling of erbB receptors leads to the secretion of bioactive molecules, such as prostaglandin E2 (PGE2), which are in turn able to directly stimulate GnRH release at the nerve endings. In addition, ligand-dependent activation of erbB-1 receptors in tanycytes results in biphasic plastic changes characterized by an initial phase of tanycytic outgrowth and a secondary phase of retraction. Although the initial outgrowth is independent of the TGFβ1 system, the subsequent retraction requires PGE2 synthesis, a PGE2-dependent increase in the production of TGFβ1 and matrix metalloproteinase activity (MMP). Endothelial-neuronal interactions at the level of the median eminence involves the production of nitric oxide (NO) by endothelial cells of fenestrated capillaries of the portal blood vessels. Upon its secretion, NO diffuses from its source, where it not only stimulates the release of GnRH from the neighboring GnRH neuroendocrine terminals but also promotes their access to the blood stream by inducing cytoarchitectural changes in tanycytic end-feet. In addition, because GnRH neurons express intrinsic markers of axon plasticity such as the growth-associated protein 43 (GAP-43) and are known to sprout new terminals towards the pericapillary space in proestrus, it is conceivable that individual GnRH nerve endings may be responsive to growth promoting factors produced locally within the median eminence. Estrogens are likely to be the key humoral factors involved in the orchestration of the glia-to-neuron communication that allows GnRH neurons to directly contact the pituitary portal blood vessels on the day of proestrus. eNOS, endothelial nitric oxide synthase. Adapted from [15] with permission.

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