Specific repression of the preproendothelin-1 gene in intracranial arteriovenous malformations.
Specific repression of the preproendothelin-1 gene in intracranial arteriovenous malformations.
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DOI：
10.3171/jns.1997.86.1.0101
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发表时间：
1997
影响因子：
4.1
通讯作者：
R. L. Rhoten;Y. Comair;D. Shédid;D. Chyatte;M. Simonson
中科院分区：
文献类型：
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作者：
R. L. Rhoten;Y. Comair;D. Shédid;D. Chyatte;M. Simonson
脑动静脉畸形（AVM）表现为血管发育异常和血流自动调节障碍。导致脑AVM发病机制和表型的遗传机制尚不清楚。作为理解AVM病理生理学的第一步，作者研究了内皮功能障碍（特别是内皮素-1（ET-1）分泌失调）导致异常血管表型和这些病变导致的血流动力学自动调节缺乏的假设。在所有17例AVM患者的病灶内血管中均未检测到内皮素-1肽和内皮素原-1（ppET 1）信使RNA，但在正常血管的人类对照受试者中显著表达（p < 0.01）。虽然AVM血管缺乏ET-1，但其表达在远离这些病变的血管中很突出，表明ppET-1基因的局部抑制。ET-1的局部抑制是AVM特有的;与正常对照组相比，Sturge-Weber病患者血管畸形中的ET-1实际上升高（p < 0.01）。ppET-1基因的抑制是AVM内皮细胞的固有表型，而不是由于AVM微环境中的因素。作者还表明，与正常对照相比，AVM血管系统中的ETA受体表达较低。总之，这些结果表明，ppET-1基因在AVM病变中受到局部抑制，并表明异常ppET-1基因调控在脑AVM发病机制和临床后遗症中的作用。
Cerebrovascular arteriovenous malformations (AVMs) display abnormal vascular development and dysautoregulation of blood flow. Genetic mechanisms that contribute to the pathogenesis and phenotype of cerebral AVMs are unknown. As a first step in understanding the pathophysiology of AVMs, the authors investigated the hypothesis that endothelial dysfunction-specifically, deregulation of endothelin-1 (ET-1) secretion-contributes to the abnormal vascular phenotype and the lack of hemodynamic autoregulation elaborated by these lesions. Endothelin-1 peptide and preproendothelin-1 (ppET1) messenger RNA were not detected in the intranidal vasculature of all 17 patients with AVMs studied, but were prominently expressed in human control subjects with normal cerebrovasculature (p < 0.01). Although AVM vasculature lacked ET-1, its expression was prominent in vasculature distant from these lesions, suggesting local repression of the ppET-1 gene. Local repression of ET-1 was specific to AVMs; ET-1 in vascular malformations of patients with Sturge-Weber disease was actually elevated compared to normal controls (p < 0.01). Repression of the ppET-1 gene was an intrinsic phenotype of AVM endothelial cells and was not due to factors in the AVM microenvironment. The authors also showed that ETA receptor expression was low in AVM vasculature compared to normal controls. Together, these results demonstrate that the ppET-1 gene is locally repressed in AVM lesions and suggest a role for abnormal ppET-1 gene regulation in the pathogenesis and clinical sequelae of cerebral AVMs.