The interaction among hydrogen sulfide, estrogen and insulin-like growth factor-1 in vascular smooth muscle cells

The proliferation of vascular smooth muscle cells (SMCs) is regulated by an array of
\nendogenous substances, including estrogen, insulin-like growth factor-1 (IGF-1), and hydrogen
\nsulfide (H2S). Estrogen inhibits SMC proliferation via the activation of estrogen receptor-α (ER-
\nα), but it stimulates the same in the absence of endogenous H2S. IGF-1, via its receptor (IGF-
\n1R), stimulates SMC proliferation and migration. ER-α and IGF-1R can form hybrid dimer with
\n
\nboth ER and IGF-1 as the binding ligands. Furthermore, H2S produced by cystathionine-gamma
\nlyase (CSE) inhibits SMC proliferation. It appears that the interaction and integration of the
\nvascular effects of estrogen, IGF-1, and H2S determine the outcome of the proliferation of
\nSMCs. In this thesis study, we found that plasma estrogen levels were significantly lower in
\nfemale CSE knockout (KO) mice than in female wide-type (WT) mice. Estrogen treatment of
\natherogenic diet-fed mice attenuated hypercholesterolemia, oxidative stress, intracellular
\nadhesion molecule-1 and NF-κB expression and increased H2S production in WT mice but not in
\nCSE- KO mice. Not only estrogen and H2S affects each other’s production and function, H2S
\nalso interacts with IGF-1 to inhibit the stimulatory effect of IGF-1 on SMCs proliferation. This
\ninhibitory effect of H2S was abolished by blocking IGF-1/IGF-1R signaling pathway. On the
\nother hand, estrogen downregulated the protein expressions of IGF-1 and IGF-1R in mouse
\naortic tissues or aortic SMCs. Deficiency of IGF-1R expression or lower IGF-1R activity
\nabolished the stimulatory effect of estrogen on the proliferation of CSE-KO SMCs. ER-α and
\nIGF-1R were co-located on cell membrane and co-immunoprecipitated. The binding of estrogen
\nto IGF-1R/ER-α hybrid catalyzed the stimulatory effect on SMC proliferation. Finally, H2S induced the S-sulfhydration of IGF-1R, but not ER-α, in mouse SMCs, which lead to the
\ndecreased formation of IGF-1R/ER-α hybrid. This decrease inhibited the phosphorylation of
\nIGF-1R, and attenuated estrogen-induced SMC proliferation.
\nIt is concluded that the antiatherosclerotic effect of estrogen is mediated by CSEgenerated H2S. The absence of H2S favors the interaction of estrogen with IGF-1R/ER-α hybrid
\nto stimulate SMC proliferation whereas the presence of H2S favors the interaction of estrogen
\nwith ER-α to inhibit SMC proliferation. Our studies demonstrate that H2S reverses the proproliferative effect of estrogen on SMCs and unmasks the dominative anti-atherosclerotic effect
\nof estrogen. The appreciation of the critical role of H2S in the cardiovascular effects of estrogen
\nand IGF-1 will help better understand the regulation of the complex vascular effects of estrogen
\nand sex-related cardiovascular diseases

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