Chronic hydrocephalus (CH) is characterized by the presence of ventricular enlargement, decreased cerebral blood flow (CBF), and brain tissue oxygen delivery. Although the underlying pathophysiological role of vascular endothelial growth factor (VEGF) is not clear, ischemic-hypoxic events in CH are known to trigger its release.
We investigated changes in neuronal and glial VEGFR-2 density and blood vessel density (BVd) in two clinically relevant areas of the brain, the hippocampus and caudate nucleus in an experimental model of CH. We also investigated changes in neuronal and glial VEGF receptor -2 density and BVd in the caudate nucleus after cerebrospinal fluid (CSF) shunting. Animals with CH were divided into short term (ST, 2-4 weeks) and long term (LT, 12-16 weeks) and were compared with surgical controls (SCs, 12-16 weeks) and CH-shunted animals (CH-S, 12-16 weeks). The cellular and BVds were estimated using immunohistochemical and stereological counting methods.
Overall, percentage (%) VEGFR-2 neurons were approximately two–six times greater in CH (ST, LT) than in SC. There were differences in glial VEGFR-2 and BVd expression in the hippocampus and caudate nucleus. There was a six fold increase in VEGFR-2 glia in all regions of the hippocampus. By comparison, glial cell %VEGFR-2 was greater by 4-17% in CH compared with that in SC. Blood vessel density was six times greater in the hippocampus after CH but significantly lower in CH caudate compared to SC. There was a decrease in VEGFR-2 neuronal expression after shunting in the caudate regions compared to CH. After CSF shunting, the BVd initially decreased followed by an increase but only in the superficial caudate. Changes in CSF ventricular volume correlated with VEGFR-2 or BVd in the hippocampus but only partially in the superficial caudate region.
VEGFR-2 may play an adaptive role in angiogenesis after CH-induced hypoxia. The dissociation of BVd and VEGF expression observed in the caudate differs from the hippocampus where uniform increases in BVd may have been facilitated by greater VEGFR-2 activation and better collateral blood supply. Modulation of the VEGF ligand and/or VEGFR-2 receptor may be important in developing treatments for hypoxic conditions including hydrocephalus and other forms of ischemia.