Chronic stress accelerates the development of endometriosis in mouse through adrenergic receptor β2

Qiqi Long, Long Q, Xishi Liu, Liu X, Qiu-Ming Qi, Qi Q, Qiuming Qi, Sun-Wei Guo, Sun‐Wei Guo, Guo SW
Human Reproduction · 2016 · vol. 31(11) , pp. 2506–2519 · doi:10.1093/humrep/dew237 · PMID:27664956 · W2523461037
article OA: bronze CC0 ⤵ 45 in-corpus citations
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Chronic stress accelerates endometriosis development and hyperalgesia in mice, primarily via adrenergic receptor β2 activation, leading to increased angiogenesis and cell proliferation.

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Abstract

STUDY QUESTION: Does chronic stress in mice accelerate the development of endometriosis, and, if so, through what mechanism? SUMMARY ANSWER: Exposure to chronic stress accelerates the development of endometriosis and exacerbates the endometriosis-associated generalized hyperalgesia, most likely through activation of the adrenoceptor β2 (ADRB2) and cAMP responsive element-binding protein (CREB). WHAT IS KNOWN ALREADY: Women with endometriosis tend to have higher levels of psychological stress, which is known to impact negatively on health in general and to promote tumor growth and metastasis in particular. Exposure to chronic stress before and after the induction of endometriosis is reported to increase lesion sizes in rodents, but it is unclear whether adrenoceptors are involved or not in the stress-promoted development of endometriosis. STUDY DESIGN, SIZE, DURATION: Three independent, prospective, randomized mouse experimentations. A total of 184 virgin female Balb/C mice were used. PARTICIPANTS/MATERIALS, SETTING, METHODS: In Experiment 1, the mice were randomly divided into four groups: the control group, which received no stress; the before, after and both groups, which received immobilization stress before, after and both before and after the induction of endometriosis, respectively. In Experiment 2, mice were randomly divided into four groups one day after the induction of endometriosis: phosphate buffer saline (PBS) and propranolol (PROP) groups, which received the mini-pump containing, respectively, PBS only and propranolol (a non-selective ADRB antagonist) but no stress, STR+PROP and STR+PBS groups, which received stress and the mini-pump containing, respectively, propranolol and PBS. The immobilization stress started after the insertion of mini-pumps. In Experiment 3, mice were induced with endometriosis. Three days after the induction, they were randomly divided into four groups: control, ADRAa, ADRB2a, and ADRBa, which received the mini-pump containing solution only, metaraminol (a non-specific α adrenoceptor agonist), tebutaline (a specific ADRB2 agonist), or isoproterenol (a non-specific ADRB agonist), respectively. In all three experiments, the bodyweight and hotplate latency were evaluated before sacrifice 14 days after the induction. In all experimentations, the lesion weight was evaluated and the harvested ectopic endometrial tissue samples were subjected to immunohistochemistry analysis of vascular endothelial growth factor (VEGF), CD31-positive microvessels, proliferating cell nuclear antigen (PCNA), phosphorylated CREB, ADRB1, ADRB2, ADRB3, adrenergic receptor α1 (ADRA1) and ADRA2. MAIN RESULTS AND THE ROLE OF CHANCE: Exposure to chronic stress accelerated the development of endometriosis and exacerbated the endometriosis-associated generalized hyperalgesia. This promotional effect is likely to be mediated through the systemic activation of the sympatho-adreno-medullary (SAM) axis, which results in subsequent release of catecholamines. The surging catecholamines may activate ADRB2 and CREB, yielding increased angiogenesis and cellular proliferation in ectopic endometrium in mice with induced endometriosis. In addition, β adrenergic receptor blockade completely abolished the promotional effect of chronic stress, likely through suppression of ADRB2 and CREB activation, thus suppressing angiogenesis and proliferation. Moreover, a non-specific adrenergic β agonist and a specific adrenergic β2 agonist, but not non-specific adrenergic α agonist, acted similarly to chronic stress, accelerating the development of endometriosis and exacerbating the generalized hyperalgesia in mice with pre-existing endometriosis. LARGE SCALE DATA: NA. LIMITATIONS, REASONS FOR CAUTION: This study is limited by the use of immunohistochemistry analyses only and the lack of molecular data. WIDER IMPLICATIONS OF THE FINDINGS: The present study provides the experimental evidence that chronic stress can promote the development of endometriosis through the activation of ADRB2. Given ADRB2 is also expressed in human endometriosis and appears to be functional, and in light of recent awareness that adrenergic signaling plays critical roles in tumorigenesis, it is likely that adrenergic signaling may play important roles in the development of endometriosis and is potentially a target for intervention. STUDY FUNDING/COMPETING INTERESTS: This research was supported in part by grants (81270676, 81471434 and 81530040 to S.W.G.; 81370695 and 81671436 to X.S.L.) from the National Natural Science Foundation of China, and grant (2013ZYJB0019 to X.S.L.) from Shanghai Municipal Commission of Health and Family Planning. None of the authors has anything to disclose.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometrium Hyperalgesia Receptors, Adrenergic, beta-2 Stress, Physiological Stress, Psychological Adrenergic alpha-1 Receptor Agonists Adrenergic alpha-1 Receptor Agonists Adrenergic beta-Agonists Adrenergic beta-Agonists Adrenergic beta-Antagonists Adrenergic beta-Antagonists Animals Cyclic AMP Response Element-Binding Protein Cyclic AMP Response Element-Binding Protein Disease Models, Animal Endometriosis Endometriosis Endometriosis Endometrium

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