Brain arteriovenous malformation biology relevant to hemorrhage and implication for therapeutic development.
Brain arteriovenous malformations cause intracranial hemorrhage. Molecular characterization of lesional tissue implicates angiogenic (vascular endothelial growth factor, ANG-2, matrix metalloproteinase-9) and inflammatory (cytokines and chemokines) pathways, but the pathogenesis remain obscure and medical therapy is lacking. Macrophage and neutrophil invasion has also been observed in the absence of prior intracranial hemorrhage. Common polymorphisms in interleukin-1beta and activin receptor-like kinase-1 are associated with arteriovenous malformation susceptibility, and polymorphisms in interleukin-1beta, interleukin-6, tumor necrosis factor-alpha and APOE are associated with arteriovenous malformation rupture. These observations suggest that even without a complete understanding of the determinants of arteriovenous malformation development, the recent discoveries of downstream derangements in vascular function and integrity may offer potential targets for therapy development. Furthermore, biomarkers can be established for assessing intracranial hemorrhage risk. Finally, these data will aid in development of model systems for mechanistic testing by development of surrogate phenotypes (microvascular dysplasia) and/or models recapitulating the clinical syndrome of recurrent spontaneous intracranial hemorrhage.
Kim
Helen
H
Center for Cerebrovascular Research, University of California, San Francisco, Calif, USA.
Pawlikowska
Ludmila
L
Chen
Yongmei
Y
Su
Hua
H
Yang
Guo-Yuan
GY
Young
William L
WL
D030201:Activin Receptors, Type I / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000453:epidemiology*; D004195:Disease Models, Animal; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D002538:Intracranial Arteriovenous Malformations / Q000150:complications* / Q000235:genetics / Q000628:therapy*; D051379:Mice; D011110:Polymorphism, Genetic / Q000235:genetics; D012307:Risk Factors
D015415:Biomarkers; D053583:Interleukin-1beta; D015850:Interleukin-6; D030201:Activin Receptors, Type I