Nucleotides and novel signaling pathways in endothelial cells: Possible roles in angiogenesis, endothelial dysfunction and diabetes mellitus

Abstract

In this chapter, we will focus on the signal transduction pathways in endothelial cells (ECs) studied by us and other groups. We will present data showing nucleotide-mediated activation of focal adhesion kinase (FAK), AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS), and document the role of Ca2+ in these pathways. Activation by extracellular nucleotides of mitogen-activated protein kinases (MAPK), such as extracellular signal-regulated kinase (ERK), p38, and JUN NH 2-terminal kinase (JNK), phosphatidylinositol-3 kinase (PI3K), as well as the mammalian target of rapamycin (mTOR) pathway will be also discussed. Our data indicate that extracellular nucleotides activate FAK and eNOS, and modulate αv integrin expression, EC cytoskeletal rearrangements and migration, functions associated with angiogenesis. Activation of eNOS and AMPK suggests that nucleotides acting through P2 receptors may exert anti-inflammatory, anti-oxidative, pro-proliferative, and anti-apoptotic effects in the endothelium. Sustaining of eNOS activation in ECs exposed to high glucose concentrations supports our hypothesis that extracellular nucleotides play a protective role against endothelial dysfunction observed in diabetes. We have also evidence that purine nucleotides increase intracellular energy levels, possibly protecting ECs from stress-related loss of intracellular ATP. Numerous nucleotide-mediated effects on the endothelium remain to be elucidated. © Springer Science+Business Media B.V. 2010.