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Sex differences in thrombosis in mice are mediated by sex-specific growth hormone secretion patterns
源自：
1Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
2Rosalind Franklin University of Medicine and Science, Chicago Medical School, North Chicago, Illinois, USA.
3Department of Medicine, The Johns Hopkins Hospital, Baltimore, Maryland, USA.
4Jefferson Medical College, Philadelphia, Pennsylvania, USA.
5Vassar College, Poughkeepsie, New York, USA.
6Department of Medicine, Division of Cardiology, UCSF, San Francisco, California, USA.
Address correspondence to: Ethan J. Weiss, University of California, San Francisco, 505 Parnassus Ave., Room M1177a, San Francisco, California 94143-0124, USA. Phone: (415) 514-0819; Fax: (415) 476-0424; E-mail: ethan.weiss@ucsf.edu.
Published July 10, 2008
Received for publication January 7, 2008, and accepted in revised form May 27, 2008.
Sex differences in thrombosis are well described, but their underlying mechanism(s) are not completely understood. Coagulation proteins are synthesized in the liver, and liver gene expression is sex specific and depends on sex differences in growth hormone (GH) secretion — males secrete GH in a pulsatile fashion, while females secrete GH continuously. Accordingly, we tested the hypothesis that sex-specific GH secretion patterns cause sex differences in thrombosis. Male mice were more susceptible to thrombosis than females in the thromboplastin-induced pulmonary embolism model and showed shorter clotting times ex vivo. GH-deficient little (lit) mice were protected from thrombosis, and pulsatile GH given to lit mice restored the male clotting phenotype. Moreover, pulsatile GH administration resulted in a male clotting phenotype in control female mice, while continuous GH caused a female clotting phenotype in control male mice. Expression of the coagulation inhibitors Proc, Serpinc1, Serpind1, and Serpina5 were strongly modulated by sex-specific GH patterns, and GH modulated resistance to activated protein C. These results reveal what we believe to be a novel mechanism whereby sex-specific GH patterns mediate sex differences in thrombosis through coordinated changes in the expression of coagulation inhibitor genes in the liver.
The journal of clinicial investigation Published: July 10, 2008