Extracranial arteriovenous malformations demonstrate dysregulated TGF-β/BMP signaling and increased circulating TGF-β1

Abstract

Abstract Extracranial arteriovenous malformations (AVMs) are characterized by anomalous arterial-to-venous connections, aberrant angiogenesis, local inflammation and hypoxia, and disorganized histological architecture; however, the precise molecular perturbations leading to this phenotype remain elusive. We hypothesized that extracranial AVM tissue would demonstrate deregulation of the TGF-β/BMP signaling pathway, which may serve as a potential target in the development of molecular-based therapies for AVMs. AVM tissue was harvested during resection from 10 patients with AVMs and compared to control tissue. Blood was collected from 14 AVM patients and 10 patients without AVMs as controls. Expression of TGF-β/BMP pathway components was analyzed using RT-PCR, western blotting, and immunohistochemistry. Circulating levels of TGF-β1 were analyzed by ELISA. Paired t tests were utilized to perform statistical analysis. The mRNA levels of TGF-β1, ALK1, Endoglin (ENG), Smad6, Smad7, and Smad8 were significantly elevated in AVM tissue when compared to controls. Protein levels of TGF-β1 and Smad3 were elevated in AVM tissue while protein levels of BMP-9, ALK1, Smad1, Smad6, and Smad8 were significantly decreased in AVMs. Immunohistochemistry demonstrated increased TGF-β1 in the perivascular cells of AVMs compared to normal controls, and circulating levels of TGF-β1 were significantly higher in AVM patients. Patients with AVMs demonstrate aberrant TGF-β/BMP expression in AVM tissue and blood compared to controls. Targeting aberrantly expressed components of the TGF-β/BMP pathway in extracranial AVMs may be a viable approach in the development of novel molecular therapies, and monitoring circulating TGF-β1 levels may be a useful indicator of treatment success.