MRI and fluorescence microscopy of the acute vascular response to VEGF165: vasodilation, hyper-permeability and lymphatic uptake, followed by rapid inactivation of the growth factor
MRI and fluorescence microscopy of the acute vascular response to VEGF165: vasodilation, hyper-permeability and lymphatic uptake, followed by rapid inactivation of the growth factor
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DOI：
10.1002/nbm.724
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发表时间：
2002-04-01
影响因子：
2.9
通讯作者：
Neeman, M
中科院分区：
文献类型：
--
作者：
Dafni, H;Landsman, L;Neeman, M
血管内皮生长因子(VEGF)是调节肿瘤血管生成的关键生长因子之一，是抗血管生成治疗的主要靶点之一。血管内皮生长因子的长期作用包括诱导内皮细胞的增殖和迁移。未成熟毛细血管的管状形成和维持。血管内皮生长因子的早期作用包括血管扩张和通透性增加。我们推测，在抗血管生成治疗过程中，对血管内皮生长因子的早期反应可以作为一种定量检测血管内皮细胞生长因子活性的指标，因此可用于监测全身抑制血管内皮细胞生长因子信号通路的疗效。为此，我们测试了磁共振成像和荧光显微镜检测裸鼠皮内注射VEGF165的早期反应的能力。皮内注射大分子生物素-BSA-GdDTPA(23)30min后，可检测到血管局部扩张和通透性A增加。对比渗漏表现为饱和动力学。延迟对比剂注射(皮内注射血管内皮生长因子后90min)可导致低对比度渗漏，并证明这种饱和动力学不是由于血浆和间质之间的对比剂平衡所致。而是由于抑制了血管的通透性。第二次注射血管内皮细胞生长因子可恢复通透性。表明饱和动力学主要是由于生长因子的失活。荧光BSA-FITC共聚焦显微镜证实了MRI监测到的通透性变化。此外，共聚焦显微镜显示，在血管内皮生长因子诱导的高通透性区域，渗出的对比剂有有效的淋巴摄取。版权所有(C)2002 John Wiley Sons，Ltd.
Vascular endothelial growth factor (VEGF) is one of the key growth factors regulating tumor angiogenesis and thus it is one of the primary targets for antiangiogenic therapy. The long-term effects of VEGF include induction of proliferation and migration of endothelial cells. tube formation and maintenance of the immature capillaries. The early effects of VEGF include vasodilation and increased permeability. We hypothesize that the early responses to VEGF can sera e to develop a quantitative measure of the activity of VEGF, and therefore may be applicable for monitoring the efficacy of systemic suppression of VEGF signaling during antiangiogenic therapy. For that end we tested the ability of MRI and fluorescence microscopy to detect the early response to intradermal VEGF 165 in nude mice. VEGF-induced local vasodilation and increased permeability A as detected by intravenous administration of macromolecular biotin-BSA-GdDTPA(23) 30 min after intradermal administration of VEGF. Contrast leak showed saturation kinetics. Delayed contrast administration (90 min after intradermal administration of VEGF) resulted in low contrast leak and demonstrated that the saturation kinetics is not due to contrast equilibration between plasma and the interstitial space. but rather is due to suppression of vascular permeability. Permeability was restored by a second bolus of VEGF. showing that the saturation kinetics is primarily due to inactivation of the growth factor. Confocal microscopy of fluorescent BSA-FITC confirmed the permeability changes monitored by MRI. Moreover, confocal microscopy showed efficient lymphatic uptake of the extravasated contrast material specifically in regions of VEGF induced hyper-permeability. Copyright (C) 2002 John Wiley Sons, Ltd.