Behm Carolyn Z, Kaufmann Beat A, Carr Chad, Lankford Miles, Sanders John M, Rose C Edward, Kaul Sanjiv, Lindner Jonathan R
Division of Cardiovascular Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
Circulation. 2008 Jun 3;117(22):2902-11. doi: 10.1161/CIRCULATIONAHA.107.744037. Epub 2008 May 27.
Inflammatory responses contribute to vascular remodeling during tissue repair or ischemia. We hypothesized that inflammatory cell recruitment and endothelial cell activation during vasculogenesis and ischemia-mediated arteriogenesis could be temporally assessed by noninvasive molecular imaging.
Contrast ultrasound perfusion imaging and molecular imaging with microbubbles targeted to activated neutrophils, alpha(5)-integrins, or vascular cell adhesion molecule (VCAM-1) were performed in murine models of vasculogenesis (subcutaneous matrigel) or hind-limb ischemia produced by arterial occlusion in wild-type or monocyte chemotactic protein-1-deficient mice. In subcutaneous matrigel plugs, perfusion advanced centripetally between days 3 and 10. On targeted imaging, signal enhancement from alpha(5)-integrins and VCAM-1 coincided with the earliest appearance of regional blood flow. Targeted imaging correlated temporally with histological evidence of channel formation by alpha(5)-integrin-positive monocytes, followed by the appearance of spindle-shaped cells lining the channels that expressed VCAM-1. In ischemic hind-limb tissue, skeletal muscle blood flow and arteriolar density increased progressively between days 2 and 21 after arterial ligation. Targeted imaging demonstrated early signal enhancement for neutrophils, monocyte alpha(5)-integrin, and VCAM-1 at day 2 when blood flow was very low (<20% control). The neutrophil signal declined precipitously between days 2 and 4, whereas VCAM-1 and monocyte signal persisted to day 7. In mice deficient for monocyte chemotactic protein-1, monocyte-targeted signal was severely reduced compared with wild-type mice (1.2+/-0.6 versus 10.5+/-8.8 video intensity units on day 4; P<0.05), although flow responses were only mildly impaired.
Different components of the inflammatory response that participate in vascular development and remodeling can be assessed separately with targeted molecular imaging.
炎症反应在组织修复或缺血过程中促进血管重塑。我们推测，血管生成和缺血介导的动脉生成过程中的炎症细胞募集和内皮细胞激活可以通过无创分子成像进行时间评估。
在血管生成（皮下基质胶）或野生型或单核细胞趋化蛋白-1缺陷小鼠动脉闭塞所致后肢缺血的小鼠模型中，进行了对比超声灌注成像以及用靶向活化中性粒细胞、α(5)整合素或血管细胞黏附分子（VCAM-1）的微泡进行分子成像。在皮下基质胶栓中，灌注在第3天至第10天向心性推进。在靶向成像中，α(5)整合素和VCAM-1的信号增强与局部血流的最早出现相吻合。靶向成像在时间上与α(5)整合素阳性单核细胞形成通道的组织学证据相关，随后出现表达VCAM-1的通道内衬梭形细胞。在缺血后肢组织中，动脉结扎后第2天至第21天，骨骼肌血流和小动脉密度逐渐增加。靶向成像显示，在血流非常低（<20%对照）的第2天，中性粒细胞、单核细胞α(5)整合素和VCAM-1有早期信号增强。中性粒细胞信号在第2天至第4天急剧下降，而VCAM-1和单核细胞信号持续到第7天。在单核细胞趋化蛋白-1缺陷的小鼠中，与野生型小鼠相比，单核细胞靶向信号严重降低（第4天为1.2±0.6对10.5±8.8视频强度单位；P<0.05），尽管血流反应仅轻度受损。
参与血管发育和重塑的炎症反应的不同成分可以通过靶向分子成像分别进行评估。
