Modulation of the L-arginine/nitric oxide signalling pathway in vascular endothelial cells.
Nitric oxide (NO) is synthesized from L-arginine, and in endothelial cells influx of L-arginine is mediated predominantly via Na+-independent cationic amino acid transporters. Constitutive, Ca2+-calmodulin-sensitive eNOS (endothelial nitric oxide synthase) metabolizes L-arginine to NO and L-citrulline. eNOS is present in membrane caveolae and the cytosol and requires tetrahydrobiopterin, NADPH, FAD and FMN as additional cofactors for its activity. Supply of L-arginine for NO synthesis appears to be derived from a membrane-associated compartment distinct from the bulk intracellular amino acid pool, e.g. near invaginations of the plasma membrane referred to as 'lipid rafts' or caveolae. Co-localization of eNOS and the cationic amino acid transport system y+ in caveolae in part explains the 'arginine paradox', related to the phenomenon that in certain disease states eNOS requires an extracellular supply of L-arginine despite having sufficient intracellular L-arginine concentrations. Vasoactive agonists normally elevate [Ca2+]i (intracellular calcium concentration) in endothelial cells, thus stimulating NO production, whereas fluid shear stress, 17beta-oestradiol and insulin cause phosphorylation of the serine/threonine protein kinase Akt/protein kinase B in a phosphoinositide 3-kinase-dependent manner and activation of eNOS at basal [Ca2+]i levels. Adenosine causes an acute activation of p42/p44 mitogen-activated protein kinase and NO release, with membrane hyperpolarization leading to increased system y+ activity in fetal endothelial cells. In addition to acute stimulatory actions of D-glucose and insulin on L-arginine transport and NO synthesis, gestational diabetes, intrauterine growth retardation and pre-eclampsia induce phenotypic changes in the fetal vasculature, resulting in alterations in the L-arginine/NO signalling pathway and regulation of [Ca2+]i. These alterations may have significant implications for long-term programming of the fetal cardiovascular system.
Wyatt
Amanda W
AW
Centre for Cardiovascular Biology and Medicine, Guy's, King's and St. Thomas' School of Biomedical Sciences, New Hunt's House, King's College London, Guy's Campus, London SEI IUL, U.K.
Steinert
Joern R
JR
Mann
Giovanni E
GE
D001120:Arginine / Q000378:metabolism*; D002319:Cardiovascular System / Q000196:embryology*; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D005333:Fetus; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*
D009569:Nitric Oxide; D001120:Arginine