Nucleotides and Novel Signaling Pathways in Endothelial Cells: Possible Roles in Angiogenesis, Endothelial Dysfunction and Diabetes Mellitus - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 14

Chapter 2
Nucleotides and Novel Signaling Pathways
in Endothelial Cells: Possible Roles
in Angiogenesis, Endothelial Dysfunction
and Diabetes Mellitus

Elzbieta Kaczmarek

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 show-
ing nucleotide-mediated activation of focal adhesion kinase (FAK), AMP-activated
protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS), and docu-
ment the role of Ca 2+ 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 α v integrin expression, EC cytoskeletal rearrange-

ments 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 con-
centrations 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.

Keywords Endothelial cells · P2Y receptors · P2X receptors · ATP · UTP ·

ADP · Adenosine · Calcium flux · Focal adhesion kinase (FAK) · α v integrin · AMP-

activated protein kinase (AMPK) · Endothelial nitric oxide synthase (eNOS) · Nitric

oxide (NO) · Protein kinase C delta (PKC δ ) · Calcium/calmodulin-activated kinase

II · LKB1 · Extracellular signal-regulated kinase (ERK) · Mammalian target of

rapamycin (mTOR) · Nuclear factor kappa B (NF- κ B) · Diabetes

B

E. Kaczmarek ( )

Center for Vascular Biology Research, Surgery Department, Microvascular Surgery Division, Beth
Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, MA,
USA
e-mail: [e-mail]