Chronic hydrocephalus–induced hypoxia: Increased expression of VEGFR-2+ and blood vessel density in hippocampus

Chronic hydrocephalus (CH) is a neurological disease characterized by increased cerebrospinal fluid volume and pressure that is often associated with impaired cognitive function. By and large, CH is a complex and heterogeneous cerebrospinal fluid (CSF) disorder where the exact site of brain insult is uncertain. Several mechanisms including neural compression, fiber stretch, and local or global hypoxia have been implicated in the underlying pathophysiology of CH. Specifically, the hippocampus, which plays a significant role in memory processing and is in direct contact with expanding CSF ventricles, may be involved. Using our model of chronic hydrocephalus, we quantified the density of vascular endothelial growth factor receptor 2 (VEGFR-2+) neurons, glial, endothelial cells, and blood vessels in hippocampal regions CA1, CA2-3, dentate gyrus and hilus using immunohistochemical and stereological methods. Density and %VEGFR-2+ cell populations were estimated for CH animals (2–3 weeks vs. 12–16 weeks) and surgical controls (SC).Overall, we found approximately six- to eightfold increase in the cellular density of VEGFR-2+ and more than double blood vessel density (BVd) in the hippocampus of CH compared with SC. There were no significant regional differences in VEGFR-2+ cellular and BVd expression in the CH group. VEGFR-2+ and BVds were significantly related to changes in CSF volume (P≤0.05), and not intracranial pressure (ICP). The %VEGFR-2+ was significantly greater in CH than SC (P≤0.05), and was significantly correlated with BVd (P≤0.05).These results showed that CH elicited a profound increase in VEGFR-2+ in hippocampus that corresponded to increased BVd. It was unclear whether increased VEGFR-2+ and blood vessel expression was related to focal compression alone or in combination with global ischemia/hypoxia conditions as previously described. These findings suggest that VEGFR-2 may play an adaptive role in angiogenesis after CH-induced hypoxia. Modulation of vascular endothelial growth factor/VEGFR-2+ may be important in developing treatments for hypoxic conditions including hydrocephalus and other forms of cerebral ischemia.