News and Publications

Regulation of Vascular Growth and Remodeling by Soluble Receptors for Fibroblast Growth Factor

A. Hanneken, M. Mercado, M. Nguyen

Abnormal vascular growth and remodeling are components of multiple systemic diseases, including diabetes, atherosclerosis, hypertension, and cancer. A clear understanding of the mechanisms leading to abnormal vascular growth and remodeling must address the interaction between local growth factors in the vasculature and modulators of the factors in the extracellular matrix.

We have been studying the regulation of basic fibroblast growth factor, an angiogenic protein that is widely distributed in cells and in the extracellular matrix. We recently discovered a class of proteins that bind fibroblast growth factors (FGFs). These proteins, known as the soluble or truncated FGF receptors, circulate in blood and are bound to the extracellular matrix of endothelial cells. We have detected 3 soluble FGF receptors that range in size from 55 to 85 kD. These proteins consist of different isoforms of the extracellular domain of the high-affinity cell-surface receptor for FGF. We are completing the structural characterization of these 3 proteins to determine whether all of them are proteolytically cleaved from the cell surface or whether 1 of them corresponds to a putative secreted protein, which has been identified from cDNA endothelial cell libraries.

We propose that the biological activity of FGF-2 is tightly regulated in vivo by the soluble FGF receptors. Our results show that the secreted FGF receptors function as potent FGF antagonists, inhibiting the angiogenic activity of FGF-2. We are studying the functional relevance of these proteins in vivo. The mean circulating level of FGF-2 in healthy persons is 2--10 pg/ml, and the mean circulating level of soluble FGF receptors is approximately 300 ng/ml. Recent results indicated that the secreted FGF receptors inhibit the mitogenic activity of circulating FGF-2 at concentrations that are physiologically relevant in vivo.

We also found that the matrix-bound truncated FGF receptors inhibit the biological activity of matrix stores of FGF-2. These results further suggest that the soluble and truncated FGF receptors may function in vivo as scavengers of FGF-2. We think that the release of FGF-2 from these naturally occurring antagonists is responsible for regulating the endogenous stores of FGF-2.

PUBLICATIONS

Hanneken, A. The truncated FGF receptors inhibit angiogenesis induced by matrix-bound FGF-2. Invest. Ophthalmol. 39: 651, 1998.