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-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF) and stromal-cell-derived factor-1alpha (SDF-1alpha) 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-1alpha, VEGF, and SDF-1alpha 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-1alpha 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-1alpha, increasing leukocyte infiltration and MMP-9 activity.
Gao
Peng
P
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, California 94110, USA.
Zhu
Yiqian
Y
Ling
Feng
F
Shen
Fanxia
F
Lee
Brian
B
Gabriel
Rodney Allanigue
RA
Hao
Qi
Q
Yang
Guo-Yuan
GY
Su
Hua
H
Young
William L
WL
D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology; D015153:Blotting, Western; D002550:Cerebral Veins / Q000378:metabolism / Q000473:pathology*; D002560:Cerebrovascular Circulation / Q000502:physiology; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007150:Immunohistochemistry; D008264:Macrophages / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000201:enzymology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D054377:Chemokine CXCL12; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D020780:Matrix Metalloproteinase 9