Desmopressin (DDAVP) induces NO production in human endothelial cells via V2 receptor- and cAMP-mediated signaling.
The hemostatic agent desmopressin (DDAVP) also has strong vasodilatory effects. DDAVP is a selective agonist for the vasopressin V2 receptor (V2R), which is coupled to cAMP-dependent signaling. DDAVP-induced vasodilation may be due to endothelial NO synthase (eNOS) activation. This hypothesis implies cAMP-mediated eNOS activation. It also implies wide extrarenal, endothelial V2R expression. We show that in human umbilical vein endothelial cells (HUVECs) the cAMP-raising agents forskolin and epinephrine increase NO production, as measured by a l-NMMA-inhibitable rise in cellular cGMP content. They also increase eNOS enzymatic activity, in a partly calcium-independent manner. cAMP-mediated eNOS activation is associated with phosphorylation of residue Ser1177, in a phosphatidyl inositol 3-kinase (PI3K)-independent manner. HUVECs do not express V2R. However, after heterologous V2R expression, DDAVP induces cAMP-dependent eNOS activation via Ser1177 phosphorylation. We have previously found V2R expression in cultured lung endothelial cells. By real time quantitative RT-PCR, we now find a wide V2R distribution notably in heart, lung and skeletal muscle. These results indicate that DDAVP and other cAMP-raising agents can activate eNOS via PI3K-independent Ser1177 phosphorylation in human endothelial cells. This mechanism most likely accounts for DDAVP-induced vasodilation.
Kaufmann
J E
JE
Division of Clinical Biochemistry, and Department of Geriatric Medicine, Geneva, Switzerland.
Iezzi
M
M
Vischer
U M
UM
D000242:Cyclic AMP / Q000502:physiology; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D017483:Receptors, Vasopressin / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D014018:Tissue Distribution
D017483:Receptors, Vasopressin; D009569:Nitric Oxide; D000242:Cyclic AMP; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D003894:Deamino Arginine Vasopressin