Böttger Priyanka, Grosser Tilo, Ibe Waltraut, Boissel Jean-Paul, Lindemann Stephan, Werdan Karl, Schwertz HansJörg, Darius Harald, Buerke Michael
Department of Medicine II, Cardiology, Intensive Care Medicine, Angiology, St. Marien Hospital, Siegen, Germany.
Department of Medicine III, Martin-Luther-University, Halle, Germany.
J Vasc Res. 2025;62(4):193-203. doi: 10.1159/000544029. Epub 2025 Feb 5.
Vascular smooth muscle cell (SMC) proliferation and vascular homeostasis are thought to be regulated by nitric oxide and prostaglandins. The loss of these endogenous mediators seems to play an important role for the development of restenosis following balloon angioplasty.
We examined the effect of exogenous linsidomine, a nitric oxide (NO) releasing compound, in a model of balloon injury iliac arteries of rabbits. On the cellular levels, NO can exert effects like cell survival, growth, and proliferation inhibition, has effects on transcription and proteasome effects and mitochondria-related effects in SMCs. SMC proliferation was quantified as a change of intima-media ratio. Linsidomine injection or its vehicle was performed with an infusion-balloon catheter directly into the dilated vessel wall.
Balloon angioplasty resulted in a significant increase of intima-media ratio during the first 3 weeks. Linsidomine treatment decreased the intima-media ratio significantly compared to vehicle treated animals 3 weeks after balloon angioplasty (0.65 ± 0.05 vs 1.2 ± 0.2 intima-media ratio, p < 0.05). However, control vessels had an intima-media ratio of 0.15 ± 0.02. This effect was similar to NOS-2 transfected vessels following angioplasty. Immunohistochemical analysis demonstrated the expression of the proliferating cellular nuclear antigen in dilated vessel of vehicle treated animals, which was reduced in linsidomine-treated rabbits. In in vitro experiments, linsidomine inhibited significantly and dose-dependently rabbit SMC proliferation measured by BrdU incorporation. Further linsidomine increased rate of apoptotic SMCs, however, this effect was p53 independent.
Simultaneous angioplasty of the rabbit iliac artery and direct injection of linsidomine into the vessel wall seem to be an effective strategy to reduce neointima formation. Similar, local application of liposome encapsulation of human nitric oxide synthase-2 transfection resulted in potent inhibition of intima proliferation and SMC proliferation due to local restoration NO within the injured vasculature.
血管平滑肌细胞（SMC）增殖和血管稳态被认为受一氧化氮和前列腺素调节。这些内源性介质的缺失似乎在球囊血管成形术后再狭窄的发生中起重要作用。
我们在兔髂动脉球囊损伤模型中研究了外源性林西多明（一种释放一氧化氮的化合物）的作用。在细胞水平上，一氧化氮可发挥细胞存活、生长和增殖抑制等作用，对平滑肌细胞的转录、蛋白酶体及线粒体相关方面有影响。平滑肌细胞增殖通过内膜-中膜比值变化来定量。林西多明注射或其溶剂通过输液球囊导管直接注入扩张的血管壁。
球囊血管成形术后前3周内膜-中膜比值显著增加。与球囊血管成形术后3周接受溶剂处理的动物相比，林西多明治疗显著降低了内膜-中膜比值（内膜-中膜比值分别为0.65±0.05和1.2±0.2，p<0.05）。然而，对照血管的内膜-中膜比值为0.15±0.02。这种作用与血管成形术后转染一氧化氮合酶-2的血管相似。免疫组织化学分析显示，接受溶剂处理动物扩张血管中增殖细胞核抗原的表达，在接受林西多明治疗的兔中降低。在体外实验中，林西多明显著且剂量依赖性地抑制通过溴脱氧尿苷掺入法测定的兔平滑肌细胞增殖。此外，林西多明增加了平滑肌细胞的凋亡率，然而，这种作用与p53无关。
兔髂动脉同时进行血管成形术并将林西多明直接注入血管壁似乎是减少新生内膜形成的有效策略。类似地，脂质体包裹人一氧化氮合酶-2转染的局部应用，由于在受损脉管系统中局部恢复一氧化氮，导致对内膜增殖和平滑肌细胞增殖有强力抑制作用。
