Targeting neovascular pericytes in neurofibromatosis type 1.
Targeting neovascular pericytes in neurofibromatosis type 1.
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DOI：
10.1007/s10456-004-6643-3
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发表时间：
2004-01-01
期刊：
影响因子：
9.8
通讯作者：
Ozerdem, Ugur
中科院分区：
文献类型：
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作者：
Ozerdem, Ugur
除了肿瘤驱动的新血管形成外，1型神经纤维瘤病（NF1）的一个鲜为人知的后果是血管壁细胞（周细胞）的过度增殖。本研究旨在确定周细胞在NF1中的作用，并确定干扰关键周细胞成分（NG2蛋白聚糖）的功能是否会抑制NF1肿瘤新生血管。在E-10期Nf+/+（对照）、NF1 +/-和NF1 -/-胚胎、NF1 +/-、NF1 +/-小鼠24只眼的缺血诱导视网膜血管生成模型以及裸鼠原位生长的NF1患者（ST88-14, NMS-2PC）衍生的恶性周围神经鞘肿瘤（MPNSTs） （Crl: nu/nu）中研究NF1的新生血管形成。采用22只眼裸鼠角膜基质异种移植NMS-2PC肿瘤诱导血管生成模型，定量观察含抗ng2中和抗体的角膜内聚合物微球的抗血管生成作用。通过共聚焦显微镜、免疫组织化学和BrdU增殖实验，测定周细胞/内皮细胞比值和增殖率。活化的周细胞存在于血管新生芽的尖端。在NMS-2PC和ST88-14移植的MPNST肿瘤中，周细胞显示内皮的持续投入。ng2抗体组NMS-2PC肿瘤移植诱导的角膜新生血管平均为1.491 mm2，同型匹配非免疫球蛋白组（对照组）为3.186 mm2 （P=0.0002）。Nf1+/-小鼠血管新生视网膜簇中共存在193.8个血管核（一种测量缺血诱导的视网膜血管生成的方法），而Nf1+/+小鼠（对照组）中有89.23个
Apart from tumor-driven neovascularization, a less-appreciated consequence of neurofibromatosis type 1 (NF1) is the hyperproliferation of vascular mural cells (pericytes). This study aims at establishing a role for pericytes in NF1, and determining whether interference with the function of a key pericyte component (NG2 proteoglycan) inhibits NF1 tumor neovascularization. Neovascularization in NF1 was studied in Nf+/+(control), Nf1+/-, and Nf1-/-embryos at E-10, ischemia-induced retinal angiogenesis model in 24 eyes of Nf1+/-, Nf1+/+mice, and in malignant peripheral nerve sheath tumors (MPNSTs) derived from NF1 patients (ST88-14, NMS-2PC) orthotopically grown in nude mice (Crl: nu/nu). The anti-angiogenic effect of intracorneal polymer pellets containing anti-NG2 neutralizing antibody was quantified in the nude-mouse corneal angiogenesis model in which angiogenesis was induced by xenografting NMS-2PC tumor into the corneal stroma of 22 eyes. By using confocal microscopy, immunohistochemistry, and BrdU proliferation assay, the pericyte/endothelium ratios and proliferation rates were measured. Activated pericytes were present at the leading tip of the angiogenic sprouts. Pericytes showed continuous investment of endothelium in both NMS-2PC and ST88-14 MPNST tumor xenografts. Mean corneal angiogenesis induced by NMS-2PC tumor grafts in NG2-antibody treated eyes was 1.491 and 3.186 mm2 in isotype-matched non-immunoglobulin treated eyes (control) (P=0.0002). A total of 193.8 vascular nuclei (a measure of ischemia-induced retinal angiogenesis) was present in angiogenic retinal tufts in Nf1+/- mice compared to 89.23 in Nf1+/+ mice (control) (P