Rlp. Rhoten et al., SPECIFIC REPRESSION OF THE PREPROENDOTHELIN-1 GENE IN INTRACRANIAL ARTERIOVENOUS-MALFORMATIONS, Journal of neurosurgery, 86(1), 1997, pp. 101-108
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.