Dubroca Caroline, Lacombe Pierre, Domenga Valérie, Maciazek Jacqueline, Levy Bernard, Tournier-Lasserve Elisabeth, Joutel Anne, Henrion Daniel
INSERM E365, Université Paris 7, Paris, France.
Stroke. 2005 Jan;36(1):113-7. doi: 10.1161/01.STR.0000149949.92854.45. Epub 2004 Nov 29.
CADASIL is an inherited small-vessel disease responsible for lacunar strokes and cognitive impairment. The disease is caused by highly stereotyped mutations in Notch3, the expression of which is highly restricted to vascular smooth muscle cells (VSMCs). The underlying vasculopathy is characterized by degeneration of VSMCs and the accumulation of granular osmiophilic material (GOM) and Notch3 protein within the cell surface of these cells. In this study, we assessed early functional changes related to the expression of mutant Notch3 in resistance arteries.
Vasomotor function was examined in vitro in arteries from transgenic mice that express a mutant Notch3 in VSMC. Tail artery segments from transgenic and normal wild-type male mice were mounted on small-vessel arteriographs, and reactivity to mechanical (flow and pressure) forces and pharmacological stimuli were determined. Mice were studied at 10 to 11 months of age when VSMC degeneration, GOM deposits, and Notch3 accumulation were not yet present.
Passive arterial diameter, contraction to phenylephrine, and endothelium-dependent relaxation to acetylcholine were unaffected in transgenic mice. By contrast, flow-induced dilation was significantly decreased and pressure-induced myogenic tone significantly increased in arteries from transgenic mice compared with wild-type mice.
This is the first study to our knowledge providing evidence that mutant Notch3 impairs selectively the response of resistance arteries to flow and pressure. The data suggest an early role of vascular dysfunction in the pathogenic process of the disease.
伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）是一种遗传性小血管疾病，可导致腔隙性脑卒中和认知障碍。该疾病由Notch3基因中高度定型的突变引起，其表达高度局限于血管平滑肌细胞（VSMC）。潜在的血管病变特征为VSMC变性以及这些细胞表面出现嗜锇颗粒物质（GOM）和Notch3蛋白的积聚。在本研究中，我们评估了与突变型Notch3在阻力动脉中的表达相关的早期功能变化。
在体外检测表达突变型Notch3的转基因小鼠动脉的血管舒缩功能。将转基因和正常野生型雄性小鼠的尾动脉段安装在小血管血管造影仪上，测定其对机械力（流量和压力）和药物刺激的反应性。在10至11月龄时对小鼠进行研究，此时尚未出现VSMC变性、GOM沉积和Notch3积聚。
转基因小鼠的被动动脉直径、对去氧肾上腺素的收缩反应以及对乙酰胆碱的内皮依赖性舒张反应均未受影响。相比之下，与野生型小鼠相比，转基因小鼠动脉的流量诱导性扩张显著降低，压力诱导性肌源性张力显著增加。
据我们所知，这是第一项提供证据表明突变型Notch3选择性损害阻力动脉对流量和压力反应的研究。数据表明血管功能障碍在该疾病的致病过程中起早期作用。
