Hosaka Akihiro, Koyama Hiroyuki, Kushibiki Toshihiro, Tabata Yasuhiko, Nishiyama Nobuhiro, Miyata Tetsuro, Shigematsu Hiroshi, Takato Tsuyoshi, Nagawa Hirokazu
Department of Vascular Regeneration, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Circulation. 2004 Nov 23;110(21):3322-8. doi: 10.1161/01.CIR.0000147779.17602.18. Epub 2004 Nov 1.
Various growth factors promote collateral vessel development and are regarded as promising for the treatment of vascular occlusive diseases. However, an efficacious delivery system for them has yet to be established. We devised a strategy to augment functional collateral vessels by using acidic gelatin hydrogel microspheres (AGHMs) incorporating basic fibroblast growth factor (bFGF). The aim of the present study was to investigate the hypothesis that by intra-arterial (IA) administration of bFGF-impregnated AGHMs, bFGF could be delivered from AGHMs trapped in distal small-diameter vessels and thereby induce functional collateral vessels with an assured blood supply through the process of arteriogenesis.
Various sizes of AGHMs (3 mg) incorporating 125I-labeled bFGF were injected into the left internal iliac artery of a rabbit model of hindlimb ischemia. Less than 50% of radioactivity accumulated in the ischemic hindlimb after injection of AGHMs that were 10 mum in diameter, whereas approximately 80% of radioactivity was counted in the ischemic limb after administration of 29- or 59-microm-diameter AGHMs. Calf blood pressure ratio and the ratio of regional blood flow of the bilateral hindlimbs immediately before and after IA administration of 29-microm-diameter AGHMs showed no significant change. Then we evaluated the function of the developed collateral vessels 28 days after IA administration of bFGF-impregnated, 29-microm-diameter AGHMs. IA administration of bFGF-impregnated AGHMs induced marked collateral vessel improvement compared with IA administration of phosphate buffered saline-treated AGHMs and intramuscular administration of bFGF-impregnated AGHMs.
IA administration of bFGF-impregnated, 29-microm-diameter AGHMs strongly induced functional collateral vessels without worsening ischemia, indicating the possible therapeutic usefulness of this approach.
多种生长因子可促进侧支血管发育，被视为治疗血管闭塞性疾病的潜在有效方法。然而，尚未建立有效的生长因子递送系统。我们设计了一种策略，通过使用负载碱性成纤维细胞生长因子（bFGF）的酸性明胶水凝胶微球（AGHMs）来增加功能性侧支血管。本研究的目的是验证以下假设：通过动脉内（IA）注射负载bFGF的AGHMs，bFGF可从被困于远端小直径血管中的AGHMs释放，从而通过动脉生成过程诱导具有可靠血供的功能性侧支血管。
将负载125I标记bFGF的不同大小（3 mg）的AGHMs注入后肢缺血兔模型的左髂内动脉。注射直径为10μm的AGHMs后，不到50%的放射性积聚在缺血后肢，而注射直径为29μm或59μm的AGHMs后，约80%的放射性出现在缺血肢体。IA注射直径为29μm的AGHMs前后，双侧后肢的小腿血压比值和局部血流比值无显著变化。然后，我们评估了IA注射负载bFGF的29μm直径AGHMs 28天后所形成侧支血管的功能。与IA注射磷酸盐缓冲盐水处理的AGHMs以及肌肉注射负载bFGF的AGHMs相比，IA注射负载bFGF的AGHMs显著改善了侧支血管。
IA注射负载bFGF的29μm直径AGHMs可强烈诱导功能性侧支血管生成，且不会加重缺血，表明该方法可能具有治疗作用。
