Enhanced stromal H2S production via CBS upregulation promotes estrogen-stimulated human endometrial angiogenesis

Angiogenesis is a physiological process for endometrial regeneration in
the menstrual cycle and remodeling during pregnancy. Endogenous hydrogen
sulfide (H2S), produced by cystathionine-β synthase (CBS) and
cystathionine-γ lyase (CSE), is a potent proangiogenic factor; yet,
whether the H2S system is expressed in the endometrium and whether H2S
plays a role in endometrial angiogenesis are unknown.  This study
was to test whether estrogens stimulate endometrial H2S biosynthesis to
promote endometrial microvascular endothelial cell (EMEC)
angiogenesis.  CBS mRNA/protein and H2S production significantly
differed among endometria from postmenopausal (POM), premenopausal
secretory (sPRM) and proliferative (pPRM) nonpregnant (NP) and pregnant
(Preg) women (p<0.05) in a rank order of POM ≈ sPRM < pPRM
<<< Preg, positively correlating with angiogenesis
indices and endogenous estrogens and with no difference in CSE
expression.  CBS and CSE proteins were localized to stroma,
glands, and vessels in endometrium, and greater stromal CBS protein was
observed in the pPRM and Preg states.  Estradiol (but not
progesterone) stimulated CBS (but not CSE) expression and H2S production
in endometrial stromal cells (ESCs) in vitro, which were attenuated by ICI
182,780.  The H2S donor sodium hydrosulfide promoted in vitro
endometrial microvascular endothelial cell (EMEC) angiogenesis. 
Co-culture with sPRM, pPRM, and Preg ESCs all stimulated EMEC migration
with a rank order of sPRM < pPRM ≈ Preg.  CBS (but not
CSE) inhibition attenuated ESC-stimulated EMEC migration.
 Estradiol did not affect EMEC migration but potentiated
ESC-stimulated EMEC migration.  Altogether, estradiol-stimulated
specific receptor-dependent stromal CBS-H2S production to promote
endometrial EMEC angiogenesis in women.