In Vivo Angiogenesis Induced by Recombinant Adenovirus Vectors Coding Either for Secreted or Nonsecreted Forms of Acidic Fibroblast Growth Factor

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Abstract
In vivo gene transfer of angiogenic growth factors represents a potential approach to the treatment of ischemic diseases. The present study examined the in vitro and in vivo effects of two replication-deficient recombinant adenovirus (Ad) vectors coding for human acidic fibroblast growth factor (aFGF1–154). One vector codes for the nonsecreted form of the peptide (AdCMV.aFGF1–154), and the other vector codes for a recombinant, secreted form (AdCMV.sp+aFGF1–154). AdCMV.NLSβgal, an adenovirus vector coding for β-galactosidase (β-Gal), was used as a control. Assessment of proliferation of starved human umbilical vein endothelial cells infected with AdCMV.aFGF1–154 and AdCMV.sp+aFGF1–154 (20 pfu/cell) showed approximately 6- and 10-fold increase in cell number over control, respectively. Infection with AdCMV.sp+aFGF1–154 and with AdCMV.aFGF1–154 enhanced endothelial cell differentiation into capillary-like structures in vitro. However, this effect was significantly more pronounced with AdCMV.sp+aFGF1–154 than with AdCMV.aFGF1–154. Angiogenesis in vivo was assessed by injecting subcutaneously into mice 750 μl of reconstituted basement membrane proteins (Matrigel) and the Ad vectors (2 × 108 pfu). After 14 days, there was histologic evidence of neovascularization in the animal's tissue surrounding the Matrigel plugs with AdCMV.aFGF1–154 and AdCMV.sp+aFGF1–154. Further, the hemoglobin content of the Matrigel plugs with AdCMV.aFGF1–154 and with AdCMV.sp+aFGF1–154 was, respectively, 2.3- and 2.6-fold higher than with AdCMV.NLSβgal. Together, these observations support the concept that adenovirus vectors coding for various forms of acidic FGF1–154 may be used to induce angiogenesis in vivo and may provide a new therapeutic approach to ischemic diseases. Angiogenic factors hold promise as potential therapeutic agents to enhance collateral blood flow to ischemic tissues. Gene transfer of angiogenic growth factors may provide a strategy to induce neovascularization and target the development of new blood vessels to areas where angiogenesis would be expected to have a therapeutic effect. The authors have engineered replication-deficient adenovirus (Ad) vectors that carry the cDNAs for nonsecreted and recombinant secreted forms of human acidic fibroblast growth factor (aFGF1–154). The effects of both Ad vectors on endothelial cell proliferation and differentiation were examined in vitro and both Ad vectors induced angiogenesis in mice in vivo. Thus, Ad-mediated gene transfer of both nonsecreted and recombinant secreted human aFGF1–154 may be applied to gene therapy studies of ischemic diseases.

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