PERIVASCULAR AND INTRAVENOUS ADMINISTRATION OF BASIC FIBROBLAST GROWTH-FACTOR - VASCULAR AND SOLID ORGAN DEPOSITION
PERIVASCULAR AND INTRAVENOUS ADMINISTRATION OF BASIC FIBROBLAST GROWTH-FACTOR - VASCULAR AND SOLID ORGAN DEPOSITION
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DOI：
10.1073/pnas.90.4.1513
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发表时间：
1993-02-15
影响因子：
11.1
通讯作者：
KARNOVSKY, MJ
中科院分区：
文献类型：
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作者：
EDELMAN, ER;NUGENT, MA;KARNOVSKY, MJ
碱性成纤维细胞生长因子（bFGF）对动脉平滑肌细胞的体内促有丝分裂作用依赖于内皮的去除，提出了内皮是否作为机械屏障防止循环bFGF与下层平滑肌细胞接触或作为产生bFGF活性的局部抑制剂的生化屏障的问题。为了更好地定义完整的内皮细胞在调节血管和组织沉积的bFGF的作用，我们比较了命运的静脉注射I-125标记的bFGF血管周围控制生长因子的释放。峰值血清bFGF水平检测注射后1分钟内，生长因子被清除后，血清半衰期几乎为3分钟。聚合物控释装置提供bFGF的血管外空间没有transendothelial运输。血管壁内的沉积物迅速沿周向分布，并且远大于静脉注射后观察到的沉积物。沉积在邻近释放装置的动脉中的bFGF的量是沉积在接受bFGF的单次静脉内推注的动物的类似动脉中的40倍。内皮剥脱对血管周围释放后的沉积影响最小，静脉内给药后的沉积增加2倍。内膜增生的存在增加血管周围释放的bFGF的沉积2.4倍，但静脉注射的bFGF的沉积减少了67%。相比之下，碱性成纤维细胞生长因子是5- 30倍更丰富的实体器官静脉注射后，比它是血管周围释放。沉积在肾脏、肝脏和脾脏中最多，在心脏和肺中明显较低。因此，bFGF在静脉注射后迅速清除，并沉积在实体器官和血管壁内。与血管内bFGF的促有丝分裂潜力不同，血管沉积实际上不依赖于内皮的存在。血管周围递送在动脉壁内沉积bFGF方面比静脉内递送有效得多，并且增加的新生内膜可以为潜在的bFGF沉积提供额外的基质，但是由于稀释和流动介导的作用，与血管内生长因子的接触有限。
The in vivo mitogenicity of basic fibroblast growth factor (bFGF) for arterial smooth muscle cells relies on the removal of endothelium, raising the question of whether the endothelium serves as a mechanical barrier preventing contact of circulating bFGF with underlying smooth muscle cells or as a biochemical barrier that produces a local inhibitor of bFGF activity. To better define the role of the intact endothelium in modulating the vascular and tissue deposition of bFGF, we compared the fate of intravenous injections of I-125-labeled bFGF with perivascular controlled growth factor release. Peak serum bFGF levels were detected within 1 min of injection, and the growth factor was cleared thereafter with a serum half-life of almost 3 min. Polymeric controlled release devices delivered bFGF to the extravascular space without transendothelial transport. Deposition within the blood vessel wall was rapidly distributed circumferentially and was substantially greater than that observed following intravenous injection. The amount of bFGF deposited in arteries adjacent to the release devices was 40 times that deposited in similar arteries in animals who received a single intravenous bolus of bFGF. Endothelial denudation had a minimal effect on deposition following perivascular release, and it increased deposition following intravenous delivery 2-fold. The presence of intimal hyperplasia increased deposition of perivascularly released bFGF 2.4-fold but decreased the deposition of intravenously injected bFGF by 67%. In contrast, bFGF was 5- to 30-fold more abundant in solid organs after intravenous injection than it was following perivascular release. Deposition was greatest in the kidney, liver, and spleen and was substantially lower in the heart and lung. Thus, bFGF is rapidly cleared following intravenous injection and is deposited within both solid organs and the walls of blood vessels. Unlike the mitogenic potential of bFGF within blood vessels, vascular deposition is virtually independent of the presence of endothelium. Perivascular delivery is far more efficient than intravenous delivery at depositing bFGF within the arterial wall, and an increased neointima may provide added substrate for potential bFGF deposition but has limited contact with intravascular growth factor as a result of dilutional and flow-mediated effects.