Adenovirus-mediated expression of the secreted form of basic fibroblast growth factor (FGF-2) induces cellular proliferation and angiogenesis in vivo

Abstract

Blood supply through collateral arteries is of critical importance in occlusive arterial diseases such as coronary atherosclerosis. Induction of angiogenic growth factor within either the narrowing arteries or jeopardized myocardium may promote angiogenesis in vivo, leading to salvage of ischemic myocardium. We constructed a replication-defective adenovirus (AdCAsFGF-2) coding for human basic fibroblast growth factor (FGF)-2 that is modified, so that its secretion will be facilitated, by tagging a signal sequence derived from FGF-4. A large quantity of FGF-2 was detected in both the cell lysate and culture medium of COS cells infected with AdCAsFGF-2, indicating that FGF-2 was secreted at least partly from the infected cells. The conditioned medium from the infected COS cells stimulated DNA synthesis in and induced cellular proliferation of arterial smooth muscle cells. These effects were eliminated by adenovirus-mediated overexpression of a dominant-negative truncated FGF-receptor type 1. Implantation of a gel of basement membrane proteins containing fibroblasts infected with AdCAsFGF-2 into the ventral subcutaneous space of mice induced extensive cellular proliferation and the formation of functional arterioles. Cells surrounding the vessels were positively immunostained with antibodies recognizing either smooth muscle-specific alpha-actin or factor VIII antigen as a marker for endothelium. These results suggest that AdCAsFGF-2 may be useful for delivering functional FGF-2 into tissues and may lead to therapeutic angiogenesis in vivo.