Interactions of kallikrein kinin system and vascular endothelial growth factor (VEGF) in animal models of intermittent hypoxia

Abstract

Low levels of oxygen in tissues (hypoxia) occur in a number of pathophysiological conditions, such as tumors growth, heart disease and obstructive sleep apnea syndrome (OSA). A major physiological or pathological outcome of hypoxia is to stimulate the growth of blood vessels, a process known as angiogenesis. The formation of new blood vessels is essential to the myocardium to provide oxygen and nutrients to sustain cellular metabolism. In the intermittent hypoxia (IH), an experimental model that reproduces several conditions of OSA, angiogenesis occurs, although the mechanism is not yet elucidated. In other models of hypoxia and ischemia/reperfusion, it was demonstrated a strong interaction between the vascular endothelial growth factor (VEGF) and the kallikrein-kinin system (KKS) and its cardioprotective effects. In this project, we intend to contribute to the understanding of angiogenesis in an in vivo model of IH, studying the interactions of the KKS with VEGF in the heart. Wilde type and bradykinin B2-receptor knockouts strains of mice C57/BL6J will be exposed to events of hypoxia during a preconditioning period and then to IH during five weeks. At the end of each week the miocardium will be evaluated to verify in vivo angiogenesis, gene and protein expression of VEGF and its receptor, the components of KKS (bradykinin receptors, activity of proteases and kinins),the signaling pathways PI3K/AKT/eNOS and Src/Ras/Raf/MEK/iNOS.