Clinic for Radiology, University Hospital Münster, 48149 Münster, Germany.
European Institute for Molecular Imaging, WWU Münster, 48149 Münster, Germany.
Int J Mol Sci. 2023 May 11;24(10):8627. doi: 10.3390/ijms24108627.
Variations in vascular wall shear stress are often presumed to result in the formation of atherosclerotic lesions at specific arterial regions, where continuous laminar flow is disturbed. The influences of altered blood flow dynamics and oscillations on the integrity of endothelial cells and the endothelial layer have been extensively studied in vitro and in vivo. Under pathological conditions, the Arg-Gly-Asp (RGD) motif binding integrin αβ has been identified as a relevant target, as it induces endothelial cell activation. Animal models for in vivo imaging of endothelial dysfunction (ED) mainly rely on genetically modified knockout models that develop endothelial damage and atherosclerotic plaques upon hypercholesterolemia (ApoE and LDLR), thereby depicting late-stage pathophysiology. The visualization of early ED, however, remains a challenge. Therefore, a carotid artery cuff model of low and oscillating shear stress was applied in CD-1 wild-type mice, which should be able to show the effects of altered shear stress on a healthy endothelium, thus revealing alterations in early ED. Multispectral optoacoustic tomography (MSOT) was assessed as a non-invasive and highly sensitive imaging technique for the detection of an intravenously injected RGD-mimetic fluorescent probe in a longitudinal (2-12 weeks) study after surgical cuff intervention of the right common carotid artery (RCCA). Images were analyzed concerning the signal distribution upstream and downstream of the implanted cuff, as well as on the contralateral side as a control. Subsequent histological analysis was applied to delineate the distribution of relevant factors within the carotid vessel walls. Analysis revealed a significantly enhanced fluorescent signal intensity in the RCCA upstream of the cuff compared to the contralateral healthy side and the downstream region at all time points post-surgery. The most obvious differences were recorded at 6 and 8 weeks after implantation. Immunohistochemistry revealed a high degree of α-positivity in this region of the RCCA, but not in the left common carotid artery (LCCA) or downstream of the cuff. In addition, macrophages could be detected by CD68 immunohistochemistry in the RCCA, showing ongoing inflammatory processes. In conclusion, MSOT is capable of delineating alterations in endothelial cell integrity in vivo in the applied model of early ED, where an elevated expression of integrin αβ was detected within vascular structures.
血管壁切变力的变化通常被认为会导致在特定的动脉区域形成动脉粥样硬化病变，而这些区域的连续层流受到干扰。血流动力学变化和振荡对内皮细胞和内皮层完整性的影响已经在体外和体内得到了广泛研究。在病理条件下，已鉴定出 Arg-Gly-Asp（RGD）基序结合整合素αβ为相关靶点，因为它诱导内皮细胞活化。用于体内内皮功能障碍（ED）成像的动物模型主要依赖于基因修饰的敲除模型，这些模型在高胆固醇血症（ApoE 和 LDLR）下会发展出内皮损伤和动脉粥样硬化斑块，从而描绘出晚期病理生理学。然而，早期 ED 的可视化仍然是一个挑战。因此，在 CD-1 野生型小鼠中应用了低切变和振荡切变的颈动脉袖套模型，该模型应该能够显示切变力变化对健康内皮的影响，从而揭示早期 ED 的变化。多光谱光声断层扫描（MSOT）被评估为一种非侵入性且高度敏感的成像技术，用于检测静脉注射 RGD 模拟荧光探针在右颈总动脉（RCCA）手术袖套干预后的纵向（2-12 周）研究中的信号。对植入袖套上游和下游的信号分布以及对侧作为对照的信号分布进行了分析。随后进行了组织学分析，以描绘颈动脉血管壁内相关因素的分布。分析显示，与对侧健康侧和手术后所有时间点的下游区域相比，袖套上游的 RCCA 荧光信号强度显著增强。植入后 6 周和 8 周时记录到的差异最明显。免疫组织化学显示，在 RCCA 的这一区域，α 阳性程度很高，但在左颈总动脉（LCCA）或袖套下游则没有。此外，在 RCCA 中可以通过 CD68 免疫组织化学检测到巨噬细胞，表明存在持续的炎症过程。总之，MSOT 能够在应用的早期 ED 模型中描绘体内内皮细胞完整性的变化，其中在血管结构中检测到整合素αβ的表达升高。
