Abstract
The extracellular matrix plays an important role in growth factor biology, serving as a potential platform for rapid growth factor mobilization or a sink for concentrated sequestration. We now demonstrate that when a growth factor binds reversibly to the matrix, its effects are augmented by this interaction, and when the factor is absorbed irreversibly to the extracellular matrix, it becomes sequestered. These findings call into question the notion that all growth factors are best presented to cells and tissues in a sustained and controlled fashion. In our studies, we examined basic fibroblast growth factor (bFGF) and transforming growth factor-beta1 (TGF-beta1) release kinetics from synthetically fabricated microsphere devices and naturally synthesized extracellular matrix. While the sustained release of bFGF was up to 3.0-fold more potent at increasing vascular endothelial and smooth muscle cell proliferation than bolus administration, the reverse was true for TGF-beta1. A bolus of TGF-beta1 inhibited vascular cells up to 3.8-fold more efficiently than the same amount of TGF-beta1 if control-released. Both growth factors bound to the extracellular matrix, but only bFGF was released in a controlled fashion (2.8%/day). Contact with the extracellular matrix and subsequent release enhanced bFGF activity such that it was 86% more effective at increasing smooth muscle cell numbers than equal amounts of growth factor diluted from frozen stock. TGF-beta1 remained tightly adherent. The small amount of TGF-beta1 released from the extracellular matrix was approximately 30% less effective than bolus administration at inhibiting vascular endothelial and smooth muscle cell growth. Sustained growth factor release may be the preferable mode of administration, but only when a similar mode of metabolism is utilized endogenously.
Highlights
The extracellular matrix is an integral part of growth factor biology
That while the sustained release of Basic fibroblast growth factor (bFGF) was up to 3.0-fold more potent at increasing vascular endothelial and smooth muscle cell proliferation than bolus administration, the reverse was true for transforming growth factor-1 (TGF-1)
Two different devices were used because TGF-1 is not significantly heparin-binding [42], and bFGF is denatured by the methylene chloride [18, 22] required to solvent-cast Ethylene-vinyl acetate copolymer (EVAc) release devices [40]
Summary
The extracellular matrix is an integral part of growth factor biology. Many growth factors bind to this substrate, and it has been postulated that the matrix serves as a sequestration site from which growth factor stores can be concentrated for enhanced local action or released for heightened overall effect [1,2,3,4,5,6,7]. We (16 –18) and others (19 –21) have demonstrated profound biologic effects of bFGF when control-released to cells in culture or tissues in vivo These findings have been extended to matrix-binding growth factors, and it is well documented that cells optimally respond to the controlled release of growth factors [18, 22, 23]. Reports of growth factor physiology often compare bFGF and TGF-1, for together they possess the fullest range of biochemical and biophysical parameters at opposite ends of the spectrum of biologic effects [24, 25] They both have short in vivo half-lives of Ͻ30 min (26 –28) and yet have profound and sustained mediation of angiogenesis (29 –32), gene expression [33,34,35], and extracellular matrix accumulation (36 –39). A more precise understanding of the relationship between the matrix and growth factors will aid in the design of formulations for therapeutics, but will lead to an unveiling of a more definite pathophysiology of the diseases that growth factors govern
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