Recombinant fibroblast growth factor-1 promotes intimal hyperplasia and angiogenesis in arteries in vivo

Abstract

The prototype members of the heparin-binding fibroblast growth factor (FGF) family, acidic FGF (FGF-1) and basic FGF (FGF-2), are among the growth factors that act directly on vascular cells to induce endothelial cell growth and angiogenesis. In vivo, the role of the FGF prototypes in vascular pathology has been difficult to determine. We report here the introduction, by direct gene transfer into porcine arteries, of a eukaryotic expression vector encoding a secreted form of FGF-1. This somatic transgenic model defines gene function in the arterial wall in vivo. FGF-1 expression induced intimal thickening in porcine arteries 21 days after gene transfer, in contrast to control arteries transduced with an Escherichia coli beta-galactosidase gene. Where there was substantial intimal hyperplasia, neocapillary formation was detected in the expanded intima. These findings suggest that FGF-1 induces intimal hyperplasia in the arterial wall in vivo and, through its ability to stimulate angiogenesis in the neointima, FGF-1 could stimulate neovascularization of atherosclerotic plaques. Potentially, gene transfer of FGF-1 could also be used as a genetic intervention to improve blood flow to ischaemic tissues in selected clinical settings.

Angiogenesis and Fibroblast Growth Factors (FGFs) in a Three-Dimensional Collagen Gel Culture

“…However, FGF-1 is not significantly expressed in endothelial cells, suggesting a paracrine mechanism of action. Smooth muscle cells express FGF-1, and this expression may be involved in the induction of neovascularization in atherosclerotic lesions (Maciag, 1990;Nabel et al, 1993). In the RT-PCR and immunohistochemical investigations of our present study, the expression of FGF-9 was dominant within the FGF family.…”

Transcriptional targeting of replication-defective adenovirus transgene expression to smooth muscle cells in vivo.

“…These cells have been implicated in the pathogenesis of a variety of diseases including atherosclerosis, restenosis after percutaneous transluminal coronary angioplasty, and asthma (1)(2)(3)(4). Gene transfer using replicationdefective adenoviral vectors has been used to examine the pathogenesis of these diseases (40)(41)(42)(43) and also holds promise for their treatment (11). However, adenovirus-mediated gene transfer is potentially limited in both the clinical setting and in animal models of human disease, because of the capacity of these viruses to indiscriminately infect many cell types (5,15).…”

Tissue-specific gene therapy directed to tumor angiogenesis

“…Nabel et al [8][9][10] have successfully transfected human growth factors (platelet derived growth luciferase and AdCMV-luciferase to normal C57BL/6 mice, resulted in higher activity of PPE-1 promoter compared with CMV promoter in the aorta and vascularized tissues such as heart, kidney, lung and pancreas. Systemic administration of the adenoviral vector, in mice bearing Lewis lung carcinoma, resulted in high and specific activity of PPE-1 in the new vasculature of primary tumors and lung metastasis.…”

“…[8][9][10] Lemarchand et al 11,12 examined the feasibility and stability of gene expression in the ligated region of sheep carotid arteries and veins. One of the limitations of these studies was the local application, which is invasive and clinically impractical especially in tumor metastasis.…”