Potential cellular signaling mechanisms mediating upregulation of endothelial nitric oxide production by estrogen.
Experimental and clinical studies have provided ample evidence that estrogens exert a significant antiatherosclerotic effect and reduce morbidity and mortality due to cardiovascular diseases. The exact cellular mechanism of this vasculoprotective action of estrogen is not known, but recent work in our and other laboratories suggests that upregulation of endothelial nitric oxide (NO) production may significantly contribute to the mechanism. The vascular endothelium of female animals and humans produces more NO than that of males. Estrogen treatment significantly increases endothelial NO generation in ovariectomized animals and in postmenopausal women. Reduced endothelial NO production in the aorta of estrogen-receptor-deficient mice indicates that the nuclear estrogen receptor mediates the effect of estrogen. The most probable mechanism of estrogen-induced upregulation of endothelial NO production is the transcriptional stimulation of NOS III gene expression. However, the following alternative mechanisms may be involved as well: (1) inhibition of cytokine-induced downregulation of NOS III gene expression, (2) posttranslational modification of NOS III protein, (3) increased cofactor or L-arginine availability, (4) nongenomic activation of second messengers (e.g., Ca2+, cAMP) and tyrosine kinase, and (5) modulation of NO degrading systems (e.g., reactive oxygen radical generation and antioxidants). This paper reviews current data supporting these potential mechanisms.
Kauser
K
K
Berlex Biosciences, Cardiovascular Department, Richmond, Calif. 94804-0099, USA.
Rubanyi
G M
GM
D000818:Animals; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D009569:Nitric Oxide / Q000096:biosynthesis*; D011960:Receptors, Estrogen / Q000502:physiology; D012727:Sex Characteristics; D015398:Signal Transduction
D004967:Estrogens; D011960:Receptors, Estrogen; D009569:Nitric Oxide