Vascular endothelial growth factor receptor-2 (VEGFR-2) and blood vessel density changes in an experimental model of chronic hydrocephalus

Chronic Hydrocephalus (CH) is a leading cause of preventable neurological impairment. Although not clearly understood, chronic hydrocephalus may be considered a form of cerebral ischemia/hypoxia resulting from impaired cerebral blood flow as a result of mechanical compression and brain distortion (Del Bigio and Bruni 1988; Dombrowski et al 2006; Edwards et al 2004; Momjian et al 2004; Owler et al 2004b). Though most studies have described cerebrovascular compression in chronic hydrocephalus (Del Bigio and Bruni 1988; Sato et al 1984), few studies have observed increased vascular density in certain brain regions and at various time points in chronic hydrocephalus (Luciano et al 2001; Ransohoff et al 1975). Previous work in our laboratory had demonstrated an initial decrease in vascularity followed by a return above baseline in cortical gray matter in chronic hydrocephalus (Luciano et al 2001). The increase in cortical vascular density over time was more than that could be attributed to compression and may suggest a compensatory increase in vascularity accompanying chronic hypoxia. Also, the blood vessel (BV) density changes in chronic hydrocephalus have been observed to be in both directions and hence cannot be explained by simple spatial compression of the intact vascular tree.;Many studies have indicated a chronic hypoxic state in hydrocephalus (Del Bigio 1993; Edwards et al 2004; Higashi et al 1986; Richards et al 1989). Thus, it is possible 2 that in this state there may be an increase in angiogenic factors which increase the density of blood vessels. Changes in blood vessel density are known to be correlated with Vascular Endothelial Growth factor (VEGF) and its receptor VEGFR-2, which has a predominant role in the formation of new blood vessels (Dvorak 2005; Plate 1999; Rosenstein and Krum 2004). Experimental evidence suggests a direct relationship between VEGF/VEGFR-2 and BV density (Issa et al 1999; Manoonkitiwongsa et al 2004; Marti et al 2000; Shweiki et al 1992).;While the exact pathophysiology of CH is not clearly understood, cognitive deficits observed in CH may be related to direct compression of brain tissue and blood vessels, fiber stretching or reduced cerebral blood flow (Mamo et al 1987; Momjian et al 2004; Owler et al 2004b). Damage specifically to the hippocampal formation may be involved in CH-induced memory impairment. Due to the proximity of cerebrospinal fluid (CSF) ventricular spaces namely the frontal and inferior horns of the lateral ventricles and the third ventricle, to the hippocampus and caudate nucleus, they may be particularly vulnerable to compression and or stretching during chronic hydrocephalus induced ventriculomegaly. Damage specifically to the caudate nucleus may be involved in gait impairment seen in chronic hydrocephalus. Clinical and experimental evidence also suggests a pronounced decrease in volume and cerebral blood flow in the hippocampus, prefrontal cortex and the caudate in chronic hydrocephalus (DeVito et al 2007; Dombrowski et al 2006; Owler et al 2004b).;Using an experimental model of chronic hydrocephalus developed previously in our laboratory (Dombrowski et al 2006; Dombrowski et al 2008; Fukuhara et al 2001; Johnson et al 1999; Luciano et al 2001) this dissertation will investigate the relationship between vascular density and VEGFR-2 (neuronal and glial) density in clinically relevant areas of the brain after induction of hydrocephalus (hippocampus and caudate nucleus) and after CSF shunting in chronic hydrocephalus (caudate nucleus).