SPECIFIC REPRESSION OF THE PREPROENDOTHELIN-1 GENE IN INTRACRANIAL ARTERIOVENOUS-MALFORMATIONS

Cerebrovascular arteriovenous malformations (AVMs) display abnormal va scular development and dysautoregulation of blood flow. Genetic mechan isms that contribute to the pathogenesis and phenotype of cerebral AVM s are unknown. As a first step in understanding the pathophysiology of AVMs, the authors investigated the hypothesis that endothelial dysfun ction-specifically, deregulation of endothelin-1 (ET-1) secretion-cont ributes to the abnormal vascular phenotype and the lack of hemodynamic autoregulation elaborated by these lesions. Endothelin-l peptide and preproendothelin-l (ppET1) messenger RNA were not detected in the intr anidal vasculature of all 17 patients with AVMs studied, but were prom inently expressed in human control subjects with normal cerebrovascula ture (p < 0.01). Although AVM vasculature lacked ET-1, its expression was prominent in vasculature distant from these lesions, suggesting lo cal repression of the ppET-I gene. Local repression of ET-1 was specif ic to AVMs; ET-1 in vascular malformations of patients with. Sturge-We ber disease was actually elevated compared to normal controls (p < 0.0 1). Repression of the ppET-I gene was an intrinsic phenotype of AVM en dothelial cells and was not due to factors in the AVM microenvironment . The authors also showed that ET(A) receptor expression was low in AV M vasculature compared to normal controls. Together, these results dem onstrate that the ppET-1 gene is locally repressed in AVM lesions and suggest a role for abnormal ppET-1 gene, regulation in the pathogenesi s and clinical sequelae of cerebral AVMs.