Human brain arteriovenous malformations express lymphatic-associated genes

Area of Science:

• Vascular Biology
• Molecular Medicine
• Cerebrovascular Diseases

Background:

• Brain arteriovenous malformations (AVMs) are complex vascular lesions characterized by abnormal connections between arteries and veins, lacking capillaries.
• Endothelial cells (ECs) in AVMs display a loss of normal arterial and venous identity.
• The transcription factor COUP-TFII is implicated in vascular development and angiogenesis.

Purpose of the Study:

• To investigate the role of COUP-TFII in the molecular pathology of human brain AVMs.
• To analyze gene expression patterns in AVM endothelial cells.

Main Methods:

• Immunohistochemistry (IHC) and qRT-PCR were used to examine 40 human brain AVMs for COUP-TFII and other relevant gene expression.
• In vitro studies involved human umbilical ECs (HUVECs) with COUP-TFII overexpression to assess proliferation and tube formation.

Main Results:

• AVMs expressed COUP-TFII and genes associated with venous and lymphatic development (SOX18, PROX1, NFATC1, FOXC2, TBX1, LYVE1, Podoplanin, VEGF-C).
• Ki67-positive cells indicated proliferation, and signaling pathways (Hedgehog, Notch, Wnt, VEGF) were heterogeneously expressed.
• COUP-TFII overexpression in HUVECs increased proliferation and tube dilation.

Conclusions:

• AVM ECs exhibit a molecular phenotype shifting towards lymphatic characteristics, losing arterial/venous specificity.
• Gene expression correlated with clinical edema and hemorrhage.
• Findings suggest potential therapeutic targets and new research directions for AVMs.