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Perlecan domain V is upregulated in human brain arteriovenous malformation and could mediate the vascular endothelial growth factor effect in lesional tissue

Kahle, Michael P.a; Lee, Boyeonb; Pourmohamad, Tonyc; Cunningham, Austinb; Su, Huac; Kim, Helenc,f; Chen, Yongmeic; McCulloch, Charles E.c,f; Barbaro, Nicholas M.c,d; Lawton, Michael T.c,d; Young, William L.c,d,e; Bix, Gregory J.a,b

doi: 10.1097/WNR.0b013e3283554c5c
Cellular, Molecular and Developmental Neuroscience

Brain arteriovenous malformation (BAVM), a rare but important cause of intracranial hemorrhage, has increased angiogenesis and inflammation as key components of the nidus of abnormal vessels and stroma that form the resected surgical specimen. Accordingly, both vascular endothelial growth factor (VEGF) and transforming growth factor-β have been implicated in the pathology of BAVM for their proangiogenic and vascular-regulating roles. The C-terminal fragment of the extracellular matrix component perlecan (domain V, DV) has been shown to be increased and through the α5β1 integrin, to increase VEGF levels in and around areas of cerebral ischemic injury, another proangiogenic condition. We aimed to determine whether the concentrations of DV, DV’s proangiogenic receptor α5β1 integrin, or DV’s antiangiogenic receptor α2β1 integrin are elevated in human BAVM tissue. DV levels were increased in BAVM compared with control brain tissue from epileptic resection, as was α5β1 integrin. In addition, α5β1 integrin was preferentially increased and localized to endothelial cells compared with α2β1 integrin. VEGF and transforming growth factor-β levels were also increased in BAVM compared with control tissue. Furthermore, increases in all components were strongly correlated. Excessive generation of proangiogenic DV in BAVM suggests that DV may participate in its pathology and may represent a future therapeutic target.

Departments of aNeuroscience and Experimental Therapeutics

bMolecular and Cellular Medicine, Texas A&M College of Medicine, College Station, Texas

cCenter for Cerebrovascular Research, Department of Anesthesia and Perioperative Care

Departments of dNeurological Surgery

eNeurology

fEpidemiology & Biostatistics, University of California, San Francisco, California, USA

Correspondence to Gregory J. Bix, MD, PhD, Department of Molecular and Cellular Medicine, Texas A&M College of Medicine, 440 Reynolds Medical Building, College Station, TX 77843, USA Tel: +1 979 862 7613; fax: +1 979 847 9481; e-mail: gjbix@medicine.tamhsc.edu

Received April 10, 2012

Accepted April 26, 2012

© 2012 Lippincott Williams & Wilkins, Inc.