Pathologic lesions caused by catheter-based revascularization procedures for occlusive artery disease include disruption of the endothelium, exposure of extracellular matrix (ECM) proteins, and proliferation of vascular smooth muscle cells, which lead to neointima formation and restenosis. We have developed matrix-collagen-targeted retroviral vectors that are able to accumulate at sites of vascular injury (Hall et al., Hum. Gene Ther. 1997;8:2183-2192; Hall et al., Hum. Gene Ther. 2000;11:983-993). The primary tissue-targeting motif, adapted from the physiological surveillance sequence found in von Willebrand factor, served to localize and concentrate the vector within vascular lesions. In the present study, we evaluated the efficiency of this vector-targeting system in rats with nonligated balloon-injured carotid arteries. Both intraarterial (by retrograde femoral artery catheterization) and intravenous (via femoral vein) injection of a matrix-targeted vector enhanced transduction of neointimal cells ( approximately 20%) at severely denuded areas when compared with the nontargeted vector (<1%). Further, intraarterial instillation of a matrix-targeted, but not a nontargeted, vector bearing an antisense cyclin G1 construct inhibited neointima lesion formation in the injured carotid arteries. Taken together, these data indicate that strategic targeting of retroviral vectors to vascular lesions would have therapeutic potential in the management of vascular restenosis and many other disorders of uncontrolled proliferation where endothelial disruption, ECM remodeling, and collagen deposition form the nexus for preferential vector localization and concentration in vivo.

译文

闭塞性动脉疾病的基于导管的血运重建术引起的病理损害包括内皮破坏,细胞外基质(ECM)蛋白暴露以及血管平滑肌细胞增殖,从而导致新内膜形成和再狭窄。我们已经开发了靶向胶原蛋白的逆转录病毒载体,它们能够在血管损伤部位积聚(Hall等,Hum。Gene Ther。1997; 8:2183-2192; Hall等,Hum.Gene Ther。2000 ; 11:983-993)。适应于von Willebrand因子中发现的生理学监视序列的主要组织靶向基序可将载体定位并集中在血管病变内。在本研究中,我们评估了这种载体靶向系统在未结扎球囊损伤颈动脉的大鼠中的效率。与非靶向载体(<1%)相比,动脉内注射(通过逆行股动脉导管插入术)和静脉内(通过股静脉)注射在严重裸露区域的新内膜细胞(约20%)的转导都增强了内膜细胞的转导。此外,动脉内滴注带有反义细胞周期蛋白G1构建体的靶向基质的载体,而非非靶向载体,抑制了受损颈动脉中新内膜病变的形成。综上所述,这些数据表明,将逆转录病毒载体战略性地靶向血管病变将具有治疗血管再狭窄和许多其他不受控制的增生性疾病的治疗潜力,其中内皮细胞破坏,ECM重塑和胶原蛋白沉积形成了优先载体定位和相关性的纽带。体内浓度。

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