Fibroblast growth factor 2: from laboratory evidence to clinical application.
Fibroblast growth factor 2 (FGF2) is expressed ubiquitously in mesodermal and neuroectodermal cells. Human FGF2 occurs in isoforms translated from a common mRNA by alternative use of AUG (low-molecular weight isoforms) and CUG (high-molecular weight isoforms) start codons. Whereas the high-molecular weight isoforms function in an intracrine manner, the low-molecular weight isoform functions as autocrine, paracrine, and intracrine ligands. FGF2's signals are mediated by a family of high- and low-affinity receptors. The nuclear localization of FGF2 appears to be essential for its mitogenic effects with different isoforms localizing in different nuclear substructures. By regulating the transcription or activity of multiple other genes, FGF2 plays an important role in proliferation, differentiation, and survival of cells of almost all organ systems. Its potent angiogenic effects observed in tissue culture models and healthy animals have prompted clinical trials testing effects of FGF2 protein or genetic material on ischemic tissues. Unfortunately, FGF2-mediated therapeutic angiogenesis has yielded inconclusive results. One possible reason is that single-gene therapy is not sufficient to support the numerous effectors required to generate mature vessels assembled by multiple cells, including pericytes, smooth muscle cells, and endothelial cell subtypes. Another possible reason is that potentially negative effects of dyslipidemia, a common finding in patients with macro- and microvascular disease, on gene therapy have not been taken into account. We have demonstrated that electronegative low-density lipoprotein (LDL) from hypercholesterolemic human plasma downregulates FGF2 by both transcriptional and posttranscriptional mechanisms. In our models, FGF2 downregulation results in angiostasis and endothelial cell apoptosis. Deprivation of endogenous FGF2 may lead to dysregulation of the activities of other survival and angiogenesis-related genes. Delineation of the molecular mechanisms modulating the expression and actions of FGF2 may provide the basis for novel therapeutic interventions.
Chen
Chu-Huang
CH
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA. cchen@bcm.tmc.edu
Poucher
Simon M
SM
Lu
Jonathan
J
Henry
Philip D
PD
D043925:Angiogenesis Inducing Agents / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000502:physiology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy; D020033:Protein Isoforms / Q000502:physiology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D043925:Angiogenesis Inducing Agents; D020033:Protein Isoforms; D016222:Fibroblast Growth Factor 2