SOMATOSTATIN GENE-TRANSFER AND EXPRESSION IN ENDOTHELIAL-CELLS

Purpose: The antiproliferative and antisecretory effects of somatostat in have many potential uses in the clinical setting. Retroviral gene t ransfer of somatostatin to endothelium is a potential means of local d elivery of this peptide to specific vascular beds. This investigation was designed to determine whether transduced endothelial cells (ECs) c ould produce and post-translationally process somatostatin. Methods: C ultured canine venous, cat aortic, and Pat microvascular ECs were tran sfected with retroviruses containing a human somatostatin cDNA or a co ntrol beta-galactosidase gene. Total and isoform somatostatin producti on and uniformity of beta-galactosidase expression were analyzed, as w ere the effects of somatostatin production on EC proliferation. Result s: Somatostatin-transduced canine venous ECs, but not rat ECs, produce d approximately 10 times as much total somatostatin as did control-tra nsfected ECs (450 +/- 32 vs 49 +/- 10 pmol/L, p < 0.05). The predomina nt isoform of somatostatin produced was somatostatin-14. Production of somatostatin was stable with passage and did not impair the growth of canine ECs. The failure of rat ECs to produce somatostatin correlated with nonuniform expression of beta-galactosidase, suggesting that pro moter silencing was responsible for failure of transgene expression. C onclusion: Retroviral gene transfer of somatostatin to canine ECs resu lts in the production of physiologically relevant concentrations of bi ologically active somatostatin. Significant species differences exist in EC production of somatostatin, with promoter silencing being a pote ntial mechanism of failure of gene expression. Gene therapy strategies using retroviral transfer of somatostatin to ECs may allow somatostat in delivery to focal areas of the vasculature.