A co-localization of immunoreactive FGF2, AVP and their cognate receptors in the hypothalamus and choroid plexus epithelium [17–19] supports an hypothesized role  for integrating ion transport, membrane permeability and fluid balance in CNS. In peripheral tissues, the peptide trio of AVP, angiotensin II (AII) and atrial natriuretic peptide (ANP) maintain plasma volume and osmolality while FGF2 has significant hypotensive activity. By down-regulating CSF formation, the neuropeptides AVP, AII and ANP affect fluid homeostasis within the brain [1, 5, 7, 8, 16, 27]; these same peptides also modulate fluid balance in peripheral tissues [28, 29]. Both FGF2 and AII are linked to AVP release from cells that regulate CSF formation and blood flow in CNS. Accordingly, functional interactions among AVP, AII and FGF2 occur in choroid plexus, neuroendocrine regions and smooth muscle cells. FGF2, TGF-beta and other growth factors  help to regulate fluid balance by functionally coupling with fluid-regulating peptides (e.g. AVP and AII) both centrally and peripherally .
The study presented herein localized FGF2 in human and rat PVN and SON neurons, and in neurohypophysis. FGF2-like immunoreactivity was initially identified in hypothalamo-hypophyseal tissue by Iwata and colleagues  who described numerous immunoreactive neuronal processes originating from FGF2-positive cells extending lateroventrally and then caudally to the internal layer of median eminence. This pointed to a neuroendocrine-type pathway of FGF2 expression. In addition, the neurohypophysis contained many FGF2-like immunoreactive fibers. We extended Iwata's studies and, with confocal microscopy, determined that FGF2 immunoreactivity in the PVN and SON of these neuroendocrine-like pathways co-localizes with AVP.
At a subcellular level, the differential distribution of neuropeptides provides clues about function. By high-resolution analysis of hypothalamic neurons, we found that FGF2 immunostaining is associated with small granular structures at the apical portion of the perikaryon. Immunoreactive AVP, in contrast, appeared to be homogeneously distributed throughout neural cytoplasm. These localization patterns of immunoreactive FGF2 and AVP most certainly reflect different modes of peptidergic processing. Unlike AVP, the FGF2 peptide lacks a leader sequence that enables Golgi-mediated secretion. Thus, FGF2 is exported from the neuroendocrine cell by a non-Golgi-associated pathway [25, 32] with apparent linkage to the alpha subunit of Na+-K+ ATPase . Many facets of AVP secretion are well understood . However, future work should ascertain whether FGF2 is released at the apex of the perikaryon or if it regulates the release and/or processing of the AVP pro-hormone, as it does with luteinizing hormone-releasing hormone . It is interesting to note that FGF2 and vasopressin immunoreactivities do not overlap within all neurons. Some neurons continue to express only one peptide or the other. Since the physiological mechanisms through which these two peptides interact in regulating fluid balance remain unknown, one can only speculate that the relative absence in some neurons may have a physiological significance that is yet to be determined.
In 1991, Frautschy et al. first hypothesized that FGF2 could be associated with water balance . Since then, numerous studies have intimated an FGF2 involvement with hypophyseal-integrated water homeostasis [19, 23, 24]. The results presented herein are novel in describing that the hypothalamic-pituitary distribution of immunoreactive FGF2 in humans resembles that of AVP; and that dynamic changes in FGF2 expression occur in PVN, SON and choroid plexus in response to fluid dyshomeostasis. FGF2, as AII, likely promotes the release of cellular AVP, at least in choroid plexus; this leads to reduced CSF formation rate. We propose that the wide spectrum of actions of FGF2 in mitosis, angiogenesis and cell growth can now be extended to include a fluid-regulatory role [16, 17].
To evaluate the putative role of FGF2 in water balance, we began by evaluating whether conditions that change water dynamics consequently alter the distribution and level of FGF2. We found prominent tissue remodeling and increased FGF2 immunoreactivity in the pituitary neural lobe in rats subjected to 72 h of water deprivation. Moreover chronic dehydration, salt loading and hypernatremia also characteristically upregulate AVP expression in the hypothalamic-pituitary axis  and choroid plexus . Interestingly, a similar FGF2-AVP interaction has been previously noted during myocardial remodeling . These multiple, connected observations lead us to think that the observed increase in neurohypophysial FGF2 is linked to augmented release of AVP from the pituitary during dehydration and/or elevated plasma osmolality . Pituitary FGF2 up-regulation after water deprivation provides strong correlative evidence for a functional role of FGF2 in fluid balance because AVP, which co-localizes with FGF2 in the hypothalamic-pituitary axis and choroidal epithelium, regulates ion and water fluxes in V2- and V1-receptor-bearing targets such as kidney and choroid plexus .
It is fascinating that 3 isoforms of hypothalamic FGF2 were augmented by the 3-day dehydration (Fig. 8). On the other hand, enhanced expression of FGF2 in response to dehydration was not observed in the non-neural tissues compared: heart and kidney. Thus, in brain but not in cardiac and renal tissues, there was uniquely homeostatic-enhanced expression of all three known molecular weight forms (18, 23 and 24 kDa) of FGF2 (Fig. 8). These western blot data for FGF2 protein are consistent with the increased FGF2 immunostaining in SON and PVN (and choroidal epithelium) following water deprivation. Cumulative evidence therefore indicates that brain, which is responsible for regulating AVP-sensitive fluid balance via central (choroid plexus) and peripheral (kidney) organs, homeostatically modulates its FGF2 and associated AVP levels in the face of dehydration. It is interesting to note the decreased levels of FGF2 in the kidney after chronic dehydration taking into account that peripheral water homeostasis is regulated by hypothalamic AVP. The data presented here and the previous reports on the increased levels of FGF-2 mRNA in the hypothalamus after fasting  suggest that FGF2 may play a general role in regulating hypothalamic function under different stress conditions.