Interaction among estrogen, IGF-1, and H2S on smooth muscle cell proliferation

in Journal of Endocrinology
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  • 1 Cardiovascular and Metabolic Research Unit, Laurentian University, Ontario, Canada
  • 2 School of Human Kinetics, Faculty of Health, Laurentian University, Ontario, Canada
  • 3 Department of Biology, Laurentian University, Ontario, Canada
  • 4 Health Sciences North Research Institute, Sudbury, Ontario, Canada
  • 5 Department of Chemistry and Biochemistry, Laurentian University, Ontario, Canada
  • 6 Nantong University, Nantong, Jiangsu, China
  • 7 Department of Biology, York University, Toronto, Ontario, Canada

Correspondence should be addressed to L Wu or R Wang: lwu2@laurentian.ca or ruiwang@yorku.ca
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Both estrogen and hydrogen sulfide (H2S) inhibit the proliferation of vascular smooth muscle cells (SMCs) and development of atherosclerosis. In the absence of endogenous H2S as occurred in CSE-knockout (KO) mouse, however, estrogen stimulates the proliferation of vascular SMCs. The underlying mechanisms for this seemingly controversial vascular effect of estrogen are unclear. In the present study, we demonstrated that the stimulatory effect of estrogen on the proliferation of CSE-KO SMCs was suppressed by the inhibitor of insulin-like growth factor-1 receptor (IGF-1R) or knockdown of IGF-1R protein expression. Estrogen downregulated the expression of insulin-like growth factor-1 (IGF-1) and IGF-1R in aortic tissues or aortic SMCs isolated from WT and CSE-KO mice. Furthermore, endogenous H2S downregulated IGF-1R, but upregulated estrogen receptor (ER)-α, in aortic tissues or SMCs. ER-α and IGF-1R were co-located in SMCs and co-immunoprecipitated, which was decreased by H2S. Finally, both endogenous and exogenous H2S induced the S-sulfhydration of IGF-1R, but not ER-α, in WT-SMCs and CSE-KO SMCs, which underlies the decreased formation of IGF-1R/ER-α hybrid in the presence of H2S. Thus, the absence of H2S favors the interaction of estrogen with IGF-1R/ER-α hybrid to stimulate SMCs proliferation. The appreciation of a critical role of H2S in preventing estrogen-induced SMCs proliferation will help better understand the regulation of complex vascular effects of estrogen and sex-related cardiovascular diseases.

 

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