Nonischemic cerebral venous hypertension promotes a pro-angiogenic stage through HIF-1 downstream genes and leukocyte-derived MMP-9

Abstract

Cerebral venous hypertension (VH) and angiogenesis are implicated in the pathogenesis of brain arteriovenous malformation and dural arteriovenous fistulae. We studied the association of VH and angiogenesis using a mouse brain VH model. Sixty mice underwent external jugular vein and common carotid artery (CCA) anastomosis (VH model), CCA ligation, or sham dissection (n20). Hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and stromal-cell-derived factor-1α (SDF-1α) expression, and matrix metalloproteinase (MMP) activity were analyzed. We found VH animals had higher (P0.05) sagittal sinus pressure (81 mm Hg) than control groups (11 mm Hg). Surface cerebral blood flow and mean arterial pressure did not change. Hypoxia-inducible factor-1α, VEGF, and SDF-1α expression increased (P0.05). Neutrophils and MMP-9 activity increased 10-fold 1 day after surgery, gradually decreased afterward, and returned to baseline 2 weeks after surgery. Macrophages began to increase 3 days after surgery (P0.05), which coincided with the changes in SDF-1α expression. Capillary density in the parasagittal cortex increased 17% compared with the controls. Our findings suggest that mild nonischemic VH results in a pro-angiogenic stage in the brain by upregulating HIF-1 and its downstream targets, VEGF and SDF-1α, increasing leukocyte infiltration and MMP-9 activity. © 2009 ISCBFM.