Open AccessHuman brain arteriovenous malformations express lymphatic‐associated genes
Author(s) -
Shoemaker Lorelei D.,
Fuentes Laurel F.,
Santiago Shauna M.,
Allen Breanna M.,
Cook Douglas J.,
Steinberg Gary K.,
Chang Steven D.
Publication year - 2014
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.142
Subject(s) - medicine , lymphatic system , lymphangiogenesis , angiogenesis , pathology , tbx1 , immunohistochemistry , vascular endothelial growth factor , arteriovenous malformation , cancer research , gene , gene expression , biology , vegf receptors , surgery , promoter , biochemistry , cancer , metastasis
Abstract Objective Brain arteriovenous malformations ( AVM s) are devastating, hemorrhage‐prone, cerebrovascular lesions characterized by well‐defined feeding arteries, draining vein(s) and the absence of a capillary bed. The endothelial cells ( EC s) that comprise AVM s exhibit a loss of arterial and venous specification. Given the role of the transcription factor COUP ‐ TFII in vascular development, EC specification, and pathological angiogenesis, we examined human AVM tissue to determine if COUP ‐ FTII may have a role in AVM disease biology. Methods We examined 40 human brain AVMs by immunohistochemistry (IHC) and qRT ‐PCR for the expression of COUP‐TFII as well as other genes involved in venous and lymphatic development, maintenance, and signaling. We also examined proliferation and EC tube formation with human umbilical ECs (HUVEC) following COUP‐TFII overexpression. Results We report that AVM s expressed COUP ‐ TFII , SOX 18, PROX 1, NFATC 1, FOXC 2, TBX 1, LYVE 1, Podoplanin, and vascular endothelial growth factor ( VEGF )‐C, contained Ki67‐positive cells and heterogeneously expressed genes involved in Hedgehog, Notch, Wnt, and VEGF signaling pathways. Overexpression of COUP ‐ TFII alone in vitro resulted in increased EC proliferation and dilated tubes in an EC tube formation assay in HUVEC . Interpretation This suggests AVM EC s are further losing their arterial/venous specificity and acquiring a partial lymphatic molecular phenotype. There was significant correlation of gene expression with presence of clinical edema and acute hemorrhage. While the precise role of these genes in the formation, stabilization, growth and risk of hemorrhage of AVM s remains unclear, these findings have potentially important implications for patient management and treatment choice, and opens new avenues for future work on AVM disease mechanisms.