Edelman E R, Nugent M A, Karnovsky M J
Department of Internal Medicine, Brigham and Women's Hospital, Boston, MA 02115.
Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1513-7. doi: 10.1073/pnas.90.4.1513.
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 125I-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.
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，这就引发了一个问题，即内皮是作为一种机械屏障，阻止循环中的bFGF与下层平滑肌细胞接触，还是作为一种生化屏障，产生bFGF活性的局部抑制剂。为了更好地确定完整内皮在调节bFGF的血管和组织沉积中的作用，我们将静脉注射125I标记的bFGF的转归与血管周围控制生长因子释放的情况进行了比较。注射后1分钟内检测到血清bFGF水平峰值，此后生长因子被清除，血清半衰期约为3分钟。聚合物控释装置将bFGF输送到血管外间隙，无跨内皮运输。血管壁内的沉积迅速沿圆周分布，且明显大于静脉注射后的沉积。与接受单次静脉推注bFGF的动物相比，与释放装置相邻的动脉中沉积的bFGF量是相似动脉中沉积量的40倍。血管周围释放后，内皮剥脱对沉积的影响最小，而静脉给药后沉积增加了2倍。内膜增生的存在使血管周围释放的bFGF沉积增加了2.4倍，但使静脉注射的bFGF沉积减少了67%。相比之下，静脉注射后bFGF在实体器官中的含量比血管周围释放后高5至30倍。沉积在肾脏、肝脏和脾脏中最多，在心脏和肺中则明显较低。因此，静脉注射后bFGF迅速被清除，并沉积在实体器官和血管壁内。与bFGF在血管内的促有丝分裂潜能不同，血管沉积实际上与内皮的存在无关。在动脉壁内沉积bFGF方面，血管周围给药比静脉给药效率高得多，增加的新内膜可能为潜在的bFGF沉积提供额外的底物，但由于稀释和血流介导的作用，与血管内生长因子的接触有限。
