Central neuronal mechanisms may contribute to the pathogenesis of essential hypertension. Based on our recent findings, we believe changes in brain microvasculature may be partially to blame. Specifically, brainstem endothelium derived nitric oxide has recently been implicated as a major regulator of arterial pressure in hypertensive rats (Waki et al., 2006). In addition, when comparing brainstem micro vessel tissue from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats using microarrays (Toward et al., 2007), the pattern of differential gene expression suggested that the SHR brainstem uses non-oxidative metabolism indicating limited oxygen availability. Since angiotensin II (ANGII) is a major contributor to many forms of hypertension this study focused on ANGII induced hypertension and assessed the protein changes in the brainstem micro vascular fraction using 2-D difference in gel electrophoresis (2-D DIGE). WKY rats (male, 10-11 weeks) were anaesthetised with a mixture of ketamine (60 mg kg^-1) and medetomidine (250 μg kg^-1, both I.M.) and radio-transmitters installed for chronic measurement of arterial pressure using radio-telemetry. Continuous recordings of mean arterial pressure (MAP) were made for 3 days prior to, and 10 days during, S.C. micro osmotic pump driven infusion of ANGII at either a pressor (800ng●kg^-1●min^-1) or sub-pressor (50ng●kg^-1●min^-1) dose or vehicle (saline). After 10 days, a brainstem vascular fraction was isolated as previously described (Toward et al. , 2007) and protein extracted and pooled (3 rats per sample). The pressor dose increased MAP from 91±3 to 151±3 mmHg by day 8 (mean ± S.E.M., p<0.05; n=12). The sub-pressor group saw a smaller increase in MAP that was significant only on day 10 (104 ± 2 mmHg vs. 98 ± 2 mmHg pre-infusion, p<0.05; n=12) with no change in the vehicle group. The Ettan™ DIGE 2D-gel system (GE Healthcare) with DeCyder™ software and mass spectrometry were employed to detect protein changes between treatment groups (n=4 per condition). Proteins altered in rats receiving the pressor dose vs. saline, with several showing a dose-related change for both ANGII infused groups, were identified as having roles in cellular energy status with many regulated by hypoxia (e.g. increases in glycolytic enzymes and decreases in electron transport chain components). These data suggest that increased levels of ANGII may lead to reduced oxygen availability favoring non-oxidative ATP production in brainstem microvasculature. We suggest that a reduction in oxygen availability in key brainstem cardiovascular control nuclei may be a common mechanism underlying elevated sympathetic tone in neurogenic hypertension.