Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans
Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans
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DOI：
10.1172/jci41443
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发表时间：
2010-03-01
影响因子：
15.9
通讯作者：
Ingram, David A., Jr.
中科院分区：
文献类型：
--
作者：
Lasater, Elisabeth A.;Li, Fang;Ingram, David A., Jr.
1型神经纤维瘤病（NF 1）是由NF 1肿瘤抑制基因突变引起的，该基因编码神经纤维蛋白。NF 1患者表现出不同的临床表现，包括血管疾病，其由新生内膜形成和血管闭塞引起。然而，NF 1血管疾病的发病机制仍不清楚。血管壁稳态是由血管和骨髓来源的细胞（BMDC）之间的复杂相互作用维持的，神经纤维蛋白调节每种细胞类型的功能。因此，我们利用cre/lox技术和造血干细胞移植来删除内皮细胞、血管平滑肌细胞和BMDCs中Nf 1的1个等位基因，确定哪种细胞系对新生内膜至关重要。在小鼠体内形成。在这里，我们证明了在BMDCs中Nf 1的杂合失活对于血管损伤后新生内膜的形成是必要的和充分的，并提供了Nf 1（+/-）小鼠血管炎症的证据。此外，对无明显血管疾病的NF 1患者外周血的分析显示，先前与血管炎症和血管闭塞性疾病相关的炎性细胞和细胞因子浓度增加。这些数据提供了NF 1患者和NF 1（+/-）小鼠血管炎症的遗传和细胞证据，并为理解NF 1血管病变的发病机制和潜在的治疗和诊断干预提供了框架。
Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. NF1 patients display diverse clinical manifestations, including vascular disease, which results from neointima formation and vessel occlusion. However, the pathogenesis of NF1 vascular disease remains unclear. Vessel wall homeostasis is maintained by complex interactions between vascular and bone marrow-derived cells (BMDCs), and neurofibromin regulates the function of each cell type. Therefore, utilizing cre/lox techniques and hematopoietic stem cell transplantation to delete 1 allele of Nf1 in endothelial cells, vascular smooth muscle cells, and BMDCs alone, we determined which cell lineage is critical for neointima. formation in vivo in mice. Here we demonstrate that heterozygous inactivation of Nf1 in BMDCs alone was necessary and sufficient for neointima formation after vascular injury and provide evidence of vascular inflammation in Nf1(+/-) mice. Further, analysis of peripheral blood from NF1 patients without overt vascular disease revealed increased concentrations of inflammatory cells and cytokines previously linked to vascular inflammation and vasoocclusive disease. These data provide genetic and cellular evidence of vascular inflammation in NF1 patients and NF1(+/-) mice and provide a framework for understanding the pathogenesis of NF1 vasculopathy and potential therapeutic and diagnostic interventions.