缺血性脑卒中脑灌注的多模态超声分子影像学研究

Carotid stenosis caused by atherosclerosis is an important factor for various nervous system diseases duo to chronically low perfusion of brain tissue, which is mainly treated by carotid endarterectomy (CEA) or carotid artery stenting (CAS). However, the continuous increase of cerebral blood flow after CEA/CAS can lead to the cerebral hyperperfusion syndrome (CHS), the reason of which may be correlated with the dysfunction of cerebral vascular systole due to a long period of low perfusion. Systolic phenotype vascular smooth muscle cell (VSMC) is an important factor for maintaining the vascular systole and for regulating the distribution of blood flow, but the systolic phenotype VSMC would convert into the synthetic phenotype VSMC during the development of atherosclerosis. Although conventional imaging methods can accurately evaluate cerebral blood flow perfusion, but it can't assess the correlation between the VSMC phenotype and CHS during the change of cerebral blood flow perfusion. We selected the tropomyosin 4 (TPM-4) which is the specific marker of the synthetic phenotype VSMC as a targeted objective, using multimodal molecular ultrasound imaging to monitor the change of cerebral blood flow perfusion and the expression level of TPM-4 in the animal model of rabbit carotid stenosis before and after CEA, to find the correlation between the change of VSMC phenotype and the occurrence of CHS and provide a new theoretical foundation and method for the precise diagnosis and treatment of reperfusion injury of ischemic cerebral stroke.

颈动脉粥样硬化(AS)性狭窄导致的长期脑灌注不足是多种神经系统疾病发生的重要原因，颈动脉支架植入术(CAS)或颈动脉内膜剥脱术(CEA)是其主要的治疗手段，术后因患侧脑组织的血流量持续增加可能导致脑高灌注综合征(CHS)，其发生的原因可能与长期的低灌注压导致脑血管收缩功能障碍有关。收缩型血管平滑肌细胞(VSMC)是保持血管收缩性、调节血流分布的重要因素，而AS发展过程中伴随着收缩型VSMC向合成型转化。常规影像学方法虽可评价脑组织的血流灌注，但不能评价脑血流灌注变化过程中收缩型VSMC表型转化与CHS发生之间的关系，我们以合成型VSMC的特异性标志物原肌球蛋白-4 (TPM-4)为靶点，采用多模态超声分子影像学检测兔颈动脉AS性狭窄动物模型CEA前后脑组织血流灌注变化及TPM-4的表达水平，探讨VSMC表型转化与CHS发生的相关性，为缺血性脑卒中再灌注损伤的精准诊疗提供新的理论依据和方法。

颈动脉粥样硬化性狭窄引起的脑灌注不足是多种神经系统疾病发生的重要原因，颈动脉支架植入术或颈动脉内膜剥脱术是其主要的治疗手段，术后患者脑组织的血流量持续增加有导致脑高灌注综合征的风险，脑高灌注综合征是其严重的并发症，病死率高。其发生的原因可能与长期的低灌注压导致脑血管收缩功能障碍有关。收缩型血管平滑肌细胞(VSMC)是保持血管收缩性、调节血流分布的重要因素，而AS发展过程中伴随着收缩型VSMC向合成型转化，严重影响了其功能。目前影像学检查虽可评价脑组织的血流灌注，但不能评价脑血流灌注变化过程中收缩型VSMC表型转化与CHS发生之间的关系，无法评价其收缩功能。本研究获得了可用于活体动物模型的高频超声分子成像的多种纳米级靶向探针的关键技术，实现了缺血性脑卒中脑灌注的多模态超声分子影像学研究；发现了缺血性脑血流灌注异常的多模态影像学参数与CHS具有明显的正相关性；揭示了脑血流灌注变化过程中平滑肌细胞（VSMC）表型转化是造成脑缺血性再灌注损伤（CIRI）的关键因素；载探针杂合泡SIN@LPMBs联合FUS可实现对CCH模型不同病变阶段收缩型VSMC表达量变化情况的活体表征，进一步达到活体动态监测脑血管重构变化情况的目的，为临床评估脑血流重构变化提供了实验支持；对小鼠在CIRI后的不同时间点超声及光声成像特点进行了分析，为CIRI早期疾病进展及临床干预提供新证据。在此基础上，我们为了进一步揭示脑血流灌注变化，还搭建了跨模态成像系统，并尝试应用于动物实验，为评价实验动物脑血流灌注变化提供了新的方法。同时，我们在相关分子机制研究中发现铁死亡也参与了CIRI的发生发展，结果显示铁死亡在脑缺血再灌注损伤中扮演着重要的角色；YAP参与脑缺血再灌注损伤铁死亡的调控；黄芩素通过抑制铁死亡可减轻脑缺血再灌注损伤。通过对烟雾病患者、颈动脉支架植入术患者、颈动脉内膜剥脱术患者术前术后脑灌注变化的评价，进一步揭示了不同干预措施下脑血流变化情况，为术后早期采取预防及治疗措施提供依据。