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Department of Physiology and Biophysics (Q.J.P.) Hotchkiss Brain Institute University of Calgary Calgary, Alberta, Canada T2N 4N1 and Department of Physiology (S.J.M.) Neural Systems and Plasticity Research Group University of Saskatchewan Saskatoon, Saskatchewan, Canada S7N 5A5
Address all correspondence and requests for reprints to: Quentin J. Pittman, Ph.D., Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada T2N 4N1. E-mail: pittman{at}ucalgary.ca.
The hypothalamic supraoptic and paraventricular magnocellular neurons have long been favored for investigations of neuronal function due to their accessibility, defined neuronal cell types, and well known functional outputs. Here, the "neuronal" identity of endocrine-type cells was first identified within the central nervous system, their peptides were the first hormones to be structurally identified, and principles of both axonal and dendritic peptide release were first established. In addition, both astrocytes and neurons of the magnocellular nuclei display morphological and neurochemical features of plasticity that are associated with dynamic regulation of synaptic and secretory functions of the magnocellular neurons (reviewed in (Refs. 1 and 2). A paper in this issue of Endocrinology by Alonso et al. (3) reports novel data that adds yet another fascinating aspect to the physiology of these nuclei.
It has been recognized for over 30 yr that high levels of activity in these nuclei were associated with cell proliferation (4). In a recent paper (5), Alonso et al. investigated this further and reported that osmotic stimulation that highly activated the vasopressin neurons in the supraoptic nucleus (SON) caused proliferation mainly of endothelial cells, resulting in angiogenesis and increased capillary density. This was driven by an increase in the expression and action of vascular endothelial growth factor (VEGF). Alonso et al. (3) have now followed up on this intriguing finding by identifying the stimulus for the increased VEGF and resulting angiogenesis. They report that intense activation of the magnocellular neurons by an osmotic stimulus was associated with tissue hypoxia, as revealed by appearance of pimonidazole adducts that occur under hypoxic conditions. In association with this apparent tissue hypoxia, they found that expression of the transcription factor, hypoxia-inducible factor 1
, was increased in the nucleus.
What was causing the local hypoxia? Was the high neuronal activity exceeding the capacity of the local blood flow to supply enough oxygen? Or was there a local factor, unique to the magnocellular nuclei that were responsible for these changes? The authors hypothesized that the high local levels of dendritically released vasopressin (6) that are known to occur in the SON during osmotic stimulation could be responsible. To test this hypothesis, they subjected vasopressin-deficient Brattleboro rats to osmotic stimulation (drinking 2% NaCl for 3–6 d). Whereas the SON neurons in these rats respond to the osmotic stimulus in a manner similar to wild-type rats, the SON displayed no evidence of hypoxia. Furthermore, neither the VEGF up-regulation, nor cell proliferation was seen in the Brattleboro rats, indicating that it was not just the high neuronal activity that was driving both hypoxia-inducible factor 1 and VEGF gene expression. These observations suggested that local, dendritically released vasopressin mediated the changes, a conclusion supported by the reversal of the hypoxia and cell proliferation with intracerebral infusion of a V1a receptor antagonist into wild-type rats.
Although vasopressin’s vasoconstrictor activity in the circulation has long been known (thus the name vasopressin), could locally released vasopressin within the parenchyma of the SON act in a similar manner to cause hypoxia? Do the blood vessels in the SON contain vascular smooth muscle that would be a target of vasopressin? The authors first carried out immunohistochemistry to show that several of the larger blood vessels contain -actin, a marker of perivascular smooth muscle cells; furthermore, in agreement with earlier studies (7, 8), such vessels were surrounded by numerous vasopressin-immunoreactive processes, including some that appeared to directly contact the smooth muscle cells. Furthermore, pial arterioles over the SON constricted when vasopressin was applied locally in vitro, suggesting that local blood flow could be reduced by endogenously released vasopressin.
This paper suggests that neurally released vasopressin may alter the diameter of local blood vessels, a feature previously demonstrated for a number of other neuropeptides. With respect to vasopressin, it is interesting that there have previously been reports that it can constrict both pial (9) and hippocampal blood vessels (10) when applied locally. Even in vivo, intrathecally applied vasopressin has been shown to reduce local blood flow by over 50% (11). Interestingly, a reduction in local blood flow was also previously demonstrated for intrathecal dynorphin (12), another peptide dendritically released by magnocellular vasopressin neurons (13). Whether dynorphin might contribute to some of the effects on the vasculature in the SON seen in the current study is not known.
The vasoconstriction seen in response to vasopressin both in the SON and in other brain areas containing vasopressin receptors indicates that caution must used in interpreting results arising from local intracerebral application of vasopressin. That is, the physiological responses reported in many areas of the brain after local vasopressin microinfusions could be due to a receptor mediated local vasoconstriction, resulting in localized ischemia; if this were to be the case, neurons could be depolarized by local ischemia rather than by an action of the peptide directly on neurons.
A particularly intriguing question concerns the site of action for the vasoactive effects of vasopressin. Alonso et al. (3) suggest that vasopressin is acting directly on vascular smooth muscle, possibly via receptors on the parenchymal side of the smooth muscle cells. While they suggest that there is direct apposition of vasopressin containing processes onto vascular smooth muscle, previous electron microscopic studies indicate that in the majority of cases, thin astrocyte processes are interspersed between vasopressin-immunoreactive process and the blood vessel (8). Anatomical investigations examining the ultrastructural relationships between other vasoactive neurotransmitter projections and intraparenchymal blood vessels indicate that a commonality of all the perivascular terminations is that they terminate on the astrocyte endfeet that surround the microvessels (14, 15, 16, 17, 18, 19, 20). These observations suggest that the astrocyte endfeet could be an essential intermediate cellular link between dendritically released vasopressin and local blood flow. In keeping with this idea, astrocytes in explant cultures have been reported to express vasopressin binding sites (21) that when activated increase cytosolic calcium (Ca2+) concentrations (22, 23). Changes in intracellular Ca2+ concentrations in astrocytes represents the central signaling mechanism by which astrocytes communicate and recent evidence suggests that Ca2+-dependent signaling events in astrocyte endfeet play a critical role in regulating the dynamics of cerebrovascular tone (24). This raises the possibility that dendritically released vasopressin may be acting directly on astrocytes that in turn release vasoactive substances that affect vascular dynamics in the hypothalamic magnocellular nuclei.
Alonso et al. (3) have reported an excellent correlation between the release of SON vasopressin, the appearance of VEGF and the induction of angiogenesis. As VEGF is expressed, albeit in lesser amounts, throughout the adult life in SON neurons, one might ask how angiogenesis is kept in check, or even reversed after cessation of the osmotic stimulus? With respect to this, it might be of interest to consider that endothelial cells express a vasopressin-responsive receptor called vasopressin and calcium mobilizing receptor-1 (VACM-1) that attenuates proliferative activity (25, 26, 27). Perhaps in addition to induction of angiogenesis as postulated in the current article, vasopressin itself also acts at the VACM-1 to initiate a compensatory endothelial response to limit their growth.
In summary, Alonso and colleagues have revealed a fascinating interaction between activity of SON neurons and local blood flow. It would be equally interesting to know whether this would interfere with attempts to monitor activation of the SON using functional magnetic resonance imaging because this technique relies on the coupling between neuronal activity and blood flow. We look forward to more interesting concepts to be revealed through studies of the magnocellular neurons of the hypothalamus.
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Abbreviations: SON, Supraoptic nucleus; VEGF, vascular endothelial growth factor; VACM-1, vasopressin and calcium mobilizing receptor-1.
Received June 10, 2008.
Accepted for publication June 12, 2008.
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