Cai Weibo, Guzman Raphael, Hsu Andrew R, Wang Hui, Chen Kai, Sun Guohua, Gera Atul, Choi Raymond, Bliss Tonya, He Lina, Li Zi-Bo, Maag Anne-Lise D, Hori Nobutaka, Zhao Heng, Moseley Michael, Steinberg Gary K, Chen Xiaoyuan
The Molecular Imaging Program at Stanford, Department of Radiology, Stanford University, Stanford, CA, USA.
Stroke. 2009 Jan;40(1):270-7. doi: 10.1161/STROKEAHA.108.517474. Epub 2008 Oct 23.
Vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) play important roles during neurovascular repair after stroke. In this study, we imaged VEGFR expression with positron emission tomography (PET) to noninvasively analyze poststroke angiogenesis.
Female Sprague-Dawley rats after distal middle cerebral artery occlusion surgery were subjected to weekly MRI, (18)F-FDG PET, and (64)Cu-DOTA-VEGF(121) PET scans. Several control experiments were performed to confirm the VEGFR specificity of (64)Cu-DOTA-VEGF(121) uptake in the stroke border zone. VEGFR, BrdU, lectin staining, and (125)I-VEGF(165) autoradiography on stroke brain tissue slices were performed to validate the in vivo findings.
T2-weighed MRI correlated with the "cold spot" on (18)F-FDG PET for rats undergoing distal middle cerebral artery occlusion surgery. The (64)Cu-DOTA-VEGF(121) uptake in the stroke border zone peaked at approximately 10 days after surgery, indicating neovascularization as confirmed by histology (VEGFR-2, BrdU, and lectin staining). VEGFR specificity of (64)Cu-DOTA-VEGF(121) uptake was confirmed by significantly lower uptake of (64)Cu-DOTA-VEGF(mutant) in vivo and intense (125)I-VEGF(165) uptake ex vivo in the stroke border zone. No appreciable uptake of (64)Cu-DOTA-VEGF(121) was observed in the brain of sham-operated rats.
For the first time to our knowledge, we successfully evaluated the VEGFR expression kinetics noninvasively in a rat stroke model. In vivo imaging of VEGFR expression could become a significant clinical tool to plan and monitor therapies aimed at improving poststroke angiogenesis.
血管内皮生长因子（VEGF）及其受体（VEGFRs）在脑卒中后的神经血管修复过程中发挥重要作用。在本研究中，我们采用正电子发射断层扫描（PET）对VEGFR表达进行成像，以无创分析脑卒中后的血管生成情况。
对接受大脑中动脉远端闭塞手术的雌性Sprague-Dawley大鼠每周进行MRI、（18）F-FDG PET和（64）Cu-DOTA-VEGF（121）PET扫描。进行了多项对照实验，以确认（64）Cu-DOTA-VEGF（121）在脑卒中边缘区摄取的VEGFR特异性。对脑卒中脑组织切片进行VEGFR、BrdU、凝集素染色和（125）I-VEGF（165）放射自显影，以验证体内研究结果。
对于接受大脑中动脉远端闭塞手术的大鼠，T2加权MRI与（18）F-FDG PET上的“冷区”相关。脑卒中边缘区（64）Cu-DOTA-VEGF（121）的摄取在手术后约10天达到峰值，组织学检查（VEGFR-2、BrdU和凝集素染色）证实有新生血管形成。（64）Cu-DOTA-VEGF（121）摄取的VEGFR特异性通过体内（64）Cu-DOTA-VEGF（突变体）摄取显著降低以及体外脑卒中边缘区（125）I-VEGF（165）摄取强烈得到证实。在假手术大鼠的脑中未观察到（64）Cu-DOTA-VEGF（121）有明显摄取。
据我们所知，我们首次在大鼠脑卒中模型中成功无创评估了VEGFR表达动力学。VEGFR表达的体内成像可能成为规划和监测旨在改善脑卒中后血管生成的治疗的重要临床工具。
