VEGF gene therapy cooperatively recruits molecules from the immune system and stimulates cell homing and angiogenesis in refractory angina

Abstract

Background: New vessels are formed in response to stimuli from angiogenic factors, a process in which paracrine signaling is fundamental. Objective: To investigate the cooperative paracrine signaling profile in response to Vascular Endothelial Growth Factor (VEGF) gene therapy in patients with coronary artery disease (CAD) and refractory angina. Method: A cohort study was conducted in which plasma was collected from patients who underwent gene therapy with a plasmid expressing VEGF 165 (10) and from surgical procedure controls (4). Blood samples were collected from both groups prior to baseline and on days 3, 9 and 27 after the interventions and subjected to systemic analysis of protein expression (Interleukin-6, IL-6; Tumor Necrosis Factor-alpha ,TNF-alpha; Interleukin-10, IL-10; Stromal Derived Factor-1 alpha, SDF-1 alpha; VEGF; Angiopoietin-1, ANGPT-1; and Endothelin-1, ET-1) using the enzyme-linked immunosorbent assay (ELISA). Results: Analysis showed an increase in proinflammatory IL-6 (p = 0.02) and ET-1 (p = 0.05) on day 3 after gene therapy and in VEGF (p = 0.02) on day 9. A strong positive correlation was found between mobilization of endothelial progenitor cells and TNF-a on day 9 (r = 0.71; p = 0.03). Furthermore, a strong correlation between beta-blockers, antiplatelets, and vasodilators with SDF-l alpha baseline in the group undergoing gene therapy was verified (r = 0.74; p = 0.004). Conclusion: Analysis of cooperative paracrine signaling after VEGF gene therapy suggests that the immune system cell and angiogenic molecule expression as well as the endothelial progenitor cell mobilization are time-dependent, influenced by chronic inflammatory process and continuous pharmacological treatment.