Fibroblast growth factors (FGFs) are a family of structurally related proteins that influence the growth and differentiation of a variety of cell types, including the cells of the vascular system. Due to the lack of signal sequence, basic FGF is not actively secreted. However, it has been detected in the extracellular matrix bound, at least in some cases, via heparin-like molecules. Heparin has been shown to displace FGF from cells and matrices in vitro, and we have investigated the possibility that a similar phenomenon might occur in vivo. Heparin was infused intravenously into anesthesized rabbits; plasma samples taken 30 min later and monitored using [3H] thymidine incorporation into BALB/c 3T3 cells were found to contain 3-fold more stimulatory activity than control plasma samples. Addition of heparin directly to the 3T3 cells or to the plasma samples following their collection did not affect the level of stimulatory activity. A time course of stimulatory activity in rabbit plasma following heparin administration revealed that 3T3 cell stimulatory activity rapidly increased following heparin infusion, peaked at 30 min, and declined to control levels by 90-120 min. The anticoagulant action of heparin followed a different time course, providing evidence that these two effects of heparin are functionally distinct. The binding affinity of the plasma-derived stimulatory activity for heparin was used to demonstrate that the activity is FGF-like in nature. Additionally, administration of [125IJbFGF to rabbits that had been "precleared" by heparin infusion resulted in an immediate peak of circulating labeled bFGF that decreased to plateau level by 20-45 min following injection. Subsequent infusion of heparin led to an elevation of plasma [125I]bFGF levels for 20 min before returning to baseline. These results demonstrate that plasma contains an FGF-like activity whose levels can be significantly increased by the in vivo administration of heparin. Our findings indicate that cell-associated heparin-like molecules may act as a reservoir for heparin-binding molecules, including potent vaso-regulators such as the FGFs.
- Growth factors