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

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 ( n = 20). 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 ( P < 0.05) sagittal sinus pressure (8 ± 1 mm Hg) than control groups (1 ± 1 mm Hg). Surface cerebral blood flow and mean arterial pressure did not change. Hypoxia-inducible factor-1α, VEGF, and SDF-1α expression increased ( P < 0.05). 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 ( P < 0.05), 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.