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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Increased expression of HIF-1, nNOS, and VEGF in the cerebral cortex of anemic rats

¹Department of Anesthesia, Cara Phelan Trauma Research Centre, ³Division of Nephrology, ⁴Division of Cardiology, ⁶Department of Laboratory Medicine and Pathobiology, ⁷Department of Opthalmology, University of Toronto, St. Michael's Hospital, Toronto, Ontario; ²Department of Physiology, University of Toronto, Toronto, Ontario; and ⁵Biotechnology Centre for Applied Research and Training, Seneca College, Toronto, Ontario, Canada

Submitted 8 June 2006 ; accepted in final form 30 August 2006

This study tested the hypothesis that specific hypoxic molecules, including hypoxia-inducible factor-1 (HIF-1), neuronal nitric oxide synthase (nNOS), and vascular endothelial growth factor (VEGF), are upregulated within the cerebral cortex of acutely anemic rats. Isoflurane-anesthetized rats underwent acute hemodilution by exchanging 50% of their blood volume with pentastarch. Following hemodilution, mean arterial pressure and arterial Pa_O2 values did not differ between control and anemic rats while the hemoglobin concentration decreased to 57 ± 2 g/l. In anemic rats, cerebral cortical HIF-1 protein levels were increased, relative to controls (1.7 ± 0.5-fold, P < 0.05). This increase was associated with an increase in mRNA levels for VEGF, erythropoietin, CXCR4, iNOS, and nNOS (P < 0.05 for all), but not endothelial NOS. Cerebral cortical nNOS and VEGF protein levels were increased in anemic rats, relative to controls (2.0 ± 0.2- and 1.5 ± 0.4-fold, respectively, P < 0.05 for both). Immunohistochemistry demonstrated increased HIF-1 and VEGF staining in perivascular regions of the anemic cerebral cortex and an increase in the number of nNOS-positive cerebral cortical cells (3.2 ± 1.0-fold, P < 0.001). The nNOS-positive cells costained with the neuronal marker, Neu-N, but not with the astrocytic marker glial fibrillary acidic protein (GFAP). These nNOS-positive neurons frequently sent axonal projections toward cerebral blood vessels. Conversely, VEGF immunostaining colocalized with both neuronal (NeuN) and astrocytic markers (GFAP). In conclusion, acute normotensive, normoxemic hemodilution increased the levels of HIF-1 protein and mRNA for HIF-1-responsive molecules. nNOS and VEGF protein levels were also increased within the cerebral cortex of anemic rats at clinically relevant hemoglobin concentrations.

hemodilution; cerebral hypoxia

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