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

• Published in: Journal of cerebral blood flow and metabolism 2009-08, Vol.29 (8), p.1482-1490
• Main Authors: Gao, Peng, Zhu, Yiqian, Ling, Feng, Shen, Fanxia, Lee, Brian, Gabriel, Rodney Allanigue, Hao, Qi, Yang, Guo-Yuan, Su, Hua, Young, William L
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Flow Velocity - physiology; Blotting, Western; Cerebral Veins - metabolism; Cerebral Veins - pathology; Cerebrovascular Circulation - physiology; Chemokine CXCL12 - biosynthesis; Chemokine CXCL12 - genetics; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation - drug effects; Hypertension - genetics; Hypertension - metabolism; Hypertension - pathology; Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis; Immunohistochemistry; Macrophages - pathology; Male; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - genetics; Medical sciences; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic - enzymology; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Neurology; Neuropharmacology; Neuroprotective agent; Neutrophil Infiltration; Neutrophils - enzymology; Pharmacology. Drug treatments; Vascular diseases and vascular malformations of the nervous system; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - genetics
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2009.67

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.