Perivascular and intravenous administration of basic fibroblast growth factor: vascular and solid organ deposition.
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.
Edelman
E R
ER
Department of Internal Medicine, Brigham and Women's Hospital, Boston, MA 02115.
Nugent
M A
MA
Karnovsky
M J
MJ
D000464:Alginates; D000818:Animals; D002214:Capsules; D002339:Carotid Arteries / Q000502:physiology*; D004343:Drug Implants; D004730:Endothelium, Vascular / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000493:pharmacokinetics*; D020723:Glucuronic Acid; D006603:Hexuronic Acids; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular; D009206:Myocardium / Q000378:metabolism; D011865:Radioisotope Dilution Technique; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution
D000464:Alginates; D002214:Capsules; D004343:Drug Implants; D006603:Hexuronic Acids; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D020723:Glucuronic Acid