Estrogens dramatically dilate numerous vascular beds with the greatest response in

Estrogens dramatically dilate numerous vascular beds with the greatest response in the uterus. in intact and Tubeimoside I denuded UA. Quantitative immunofluorescence microscopic analyses showed CBS and CSE protein localization in endothelium and smooth muscle and confirmed that ERT stimulated CBS but not CSE protein expression in UA endothelium and smooth muscle. ERT also stimulated CBS but not CSE mRNA and protein expression in intact and denuded MA but not CA in ovariectomized ewes. Concomitantly ERT stimulated UA and MA but not CA H2S production. Tubeimoside I ERT-stimulated UA H2S production was completely blocked by a specific CBS but not CSE inhibitor. Thus ERT selectively stimulates UA and MA but not CA H2S biosynthesis by specifically up-regulating CBS expression implicating a role of H2S in estrogen-induced vasodilation and postmenopausal women’s health. Estrogens are potent vasodilators that cause blood flow to rise in selected organs throughout the body with the greatest response occurring in reproductive tissues especially the uterus (1 -4). In ovariectomized (OVX) nonpregnant ewes daily estradiol-17β (E2β) treatment increases basal uterine blood flow (UBF) 30%-40% over 6-7 days. This increase in UBF occurs with increases in cardiac output and heart rate whereas mean arterial pressure remains unchanged (2 -4) and is associated with decreased responses to vasoconstrictors (5 6 In addition acute E2β exposure provokes an even more robust rise in UBF up to 10-fold within 90-120 minutes after a bolus iv injection of 1 1 μg/kg E2β (3 4 6 -8). The vasodilatory effect of estrogens is of major physiological significance because: 1) circulating estrogen levels are significantly elevated during the follicular phase of the ovarian cycle and pregnancy to cause UBF to rise (9 10 2 during pregnancy rise in CDC46 UBF provides all the support for fetal development and survival (2 11 12 and 3) insufficient rise in UBF during pregnancy results in intrauterine growth restriction (13) preeclampsia (14) and many other pregnancy disorders (15). This insufficient rise in Tubeimoside I UBF increases the risk of infant morbidity and Tubeimoside I mortality is a significant contributor to maternal mortality and increases susceptibility to cardiovascular and other diseases for both mother and neonate later in life (12 13 Enhanced nitric oxide (NO) production via endothelial NO synthase (eNOS) in uterine artery (UA) endothelium has been identified as a major contributor to the estrogen-induced uterine vasodilatation. Blockade of local UA NO production by L-NG-nitroarginine methyl ester (L-NAME) dose dependently inhibited estrogen-induced uterine vasodilatation in animals (16 17 However blockade of UA NO production by L-NAME only inhibits approximately 65% the E2β-induced UBF response in OVX nonpregnant (16 17 and intact follicular phase (10) sheep. Thus other vasodilators derived from UA endothelium and/or the smooth muscle in addition to endothelium/NO are likely to play a role in estrogen-induced uterine vasodilatation. To this end prostacyclin is unlikely to play a key role as early studies have shown that estrogen-induced UBF in nonpregnant sheep is not affected by systemic infusion of indomethacin (17) supporting the notion that other components are involved. Hydrogen sulfide (H2S) has long been known to be a toxic gas at high doses. However because of the original discovery of its physiological action in the brain in 1996 (18) it has demonstrated that H2S possesses homologous biological and physiological functions to other “gasotransmitter” molecules such as NO and carbon monoxide (19). H2S potently relaxes rat aortic vessels by activating KATP channels which is confirmed by inhibition with the KATP channel blocker glibenclamide (20 21 Akin to NO exogenous and endogenous H2S promotes angiogenesis in vitro and in vivo through activation of KATP channels protein kinase murine thymoma viral oncogene homolog 1 (Akt1) in endothelial cells (22 -24) and interactions with NO signaling through eNOS activation in endothelial cells (24). Endogenous H2S is primarily synthesized by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) (20 25 26 Both enzymes produce H2S from L-cysteine: CBS via a β-replacement reaction with a variety of thiols and CSE by disulfide elimination followed by reaction with various thiols (24 26.