Hydrogen sulfide (H2S) is now accepted as the third member of gasotransmitter family due to its vasodilatory and angiogenic effects as endogenous and exogenous H2S promotes endothelial cell (EC) angiogenesis in vitro and in vivo. Endogenous H2S is mainly produced by metabolizing L-cysteine via two key enzymes: cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE). Endometrial angiogenesis is the prerequisite for endometrial regeneration during menstrual cycle and pregnancy. Whether the H2S system is expressed in the endometrium and whether H2S plays a role in endometrial angiogenesis has never been reported. Herein I will test a novel hypothesis that elevated estrogens stimulate estrogen receptor (ER)-dependent upregulation of endometrial stromal CBS-H2S production, which in turn stimulates endometrial microvascular EC (EMEC) angiogenesis during the proliferative phase and pregnancy in women. I will test my hypothesis by three specific aims. Aim 1 will determine if CBS/CSE-H2S system correlates to the levels of endogenous estrogens and endometrial angiogenesis index by using endometrial samples from post-menopausal, proliferative and secretory phase nonpregnant and pregnant women; Aim 2 will determine if estrogens stimulate endometrial CBS/CSE expression and H2S production via specific ERalpha and ERbeta; and Aim 3 will determine if ESC-derived H2S mediates estrogen stimulation of EMEC angiogenesis using a novel co-culture model of ESC and EMEC. The overall goal is to determine the effects of estrogens on endometrial stromal H2S biosynthesis and whether ESC-derived H2S plays a paracrine role in estrogen-stimulated EMEC angiogenesis during the menstrual cycle and pregnancy in women. This study fits the AHA mission as data will improve women's cardiovascular health.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|