Human brain arteriovenous malformations express lymphatic‐associated genes

Abstract

ObjectiveBrain arteriovenous malformations (AVMs) 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 (ECs) that comprise AVMs 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.MethodsWe 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.ResultsWe report that AVMs expressed COUP-TFII, SOX18, PROX1, NFATC1, FOXC2, TBX1, LYVE1, 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.InterpretationThis suggests AVM ECs 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 AVMs 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.

The effect of NFATc1 on vascular generation and the possible underlying mechanism in epithelial ovarian carcinoma

“…After birth, it can still regulate the growth, differentiation, and life cycle of endothelial cells. An increasing amount of data have demonstrated that NFATc1 regulates vasculogenic responses (17,18). A study using vascular endothelial growth factor (VEGF) to induce angiogenesis revealed that NFATc1 is a key component distributed at the merge point of the VEGF-induced vasculogenic endothelial cell escape pathway.…”

High-Throughput Sequencing to Detect Novel Likely Gene-Disrupting Variants in Pathogenesis of Sporadic Brain Arteriovenous Malformations

“…In addition, it is well known that human brain AVMs overexpress COUP-TFII, PROX1, and other genes, also known to regulate key aspects of angiogenesis and lymphangiogenesis. These genes have similar expression patterns and a subset of them significantly correlated with the presence of preoperative edema and acute hemorrhage (Shoemakerl et al, 2014). STK4 is not included among these genes, but homozygous nonsense mutation in STK4 cause primary immunodeficiency syndrome, given its central role in immunity (Abdollahpour et al, 2012).…”

COUP-TFII in Health and Disease

“…In agreement with its function in vessel identity specification, increased COUP-TFII expression, paralleled by modifications of SOX18 and Prox1, is associated to brain arteriovenous malformations (AVM) in humans [128,129]. Anatomically, AVM are a net of dysplastic blood vessels without capillaries between the venous and arterial compartments.…”

“…The importance of COUP-TFII in endothelial identity is well documented; the choice of arterial versus venous fate is a result of a cross-talk between Notch and COUP-TFII signaling, while the interactions of Brg1, Prox1 and COUP-TFII are central for lymphatic development [96,100,111,204]. The ability to direct angiogenesis is paralleled by its role in mesenchymal cell differentiation and point to a role of the NR in regulating the cells micro-environment with evident implications for several pathologies [45,54,74,95,117,128,132,146]. Indeed, the NR expression (or the absence thereof) is associated with the unfavorable progression of malignancies in several organs [157,163,165,167,173,181]; besides, COUP-TFII is linked to pathologies considered cancer risk factors, such as diabetes or cirrhosis [54,64].…”