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Expression of hypoxia-inducible factor-1 and vascular endothelial growth factor in response to venous hypertension.

Zhu Y, Lawton MT, Du R, Shwe Y, Chen Y, Shen F, Young WL, Yang GY

Center for Cerebrovascular Research, and Department of Anesthesia and Perioperative Care, University of California, San Francisco 94143-0112, USA.

OBJECTIVE: Experimentally, a fistula created surgically between the carotid artery and jugular vein, together with occlusion of venous sinuses, generate venous hypertension, which can induce dural arteriovenous fistula formation intracranially in rats. Our aim was to study the effect of nonischemic venous hypertension on the elaboration of the angiogenic signal, hypoxia-inducible factor-1 (HIF-1), and its downstream signal, vascular endothelial growth factor (VEGF). METHODS: Sixty rats were exposed to venous hypertension for periods ranging from 4 hours to 3 weeks. Western blot analysis, transbinding assays, enzyme-linked immunosorbent assays, and immunohistochemistry quantified HIF-1 and VEGF expression in brain. Forty-eight control rats underwent similar surgical procedures without creating venous hypertension. Cerebral blood flow was measured at baseline, after surgery, and before sacrifice. RESULTS: Venous hypertension did not impair cerebral blood flow. Relative to controls, HIF-1 expression increased fivefold in response to venous hypertension (P < 0.005), with peak expression 1 day later localized to endothelial cells in venules next to the sagittal sinus. VEGF expression also increased threefold in response to venous hypertension (P < 0.05), with peak expression 7 days later localized to parasagittal astrocytes. HIF-1 and VEGF were minimally expressed in rat normal venous pressures. CONCLUSION: In this model, venous hypertension stimulates angiogenesis by a mechanism other than ischemia. HIF-1 expression may result from dilation of parasagittal veins and endothelial deformation. HIF-1 and VEGF seem to be molecular agents that convert venous hypertension into intracellular signals and angiogenesis activity.

Published 6 September 2006 in Neurosurgery, 59(3): 687-96; discussion 687-96.
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