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Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2

Nature Genetics volume 24, pages 403–409 (2000)Cite this article

Abstract

The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine1 and behavioural responses to stress2, and the related hormone urocortin3 (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2 (refs 4,5). These receptors may exhibit distinct functions due to unique tissue distribution6 and pharmacology4,5. Crhr-null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses7,8. Here we generate Crhr2−/− mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2−/− mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2−/− mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2–/– mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2−/− mice following Ucn, but Crhr2−/− mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2−/− mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2−/− mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2.

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Figure 1: Generation of Crhr2−/− mice.
Figure 2: Crhr2−/− mice have altered HPA responses to stress.
Figure 3: Crhr2−/− mice show aberrant coping behaviour without concomitant alterations in anxiety or activity.
Figure 4: Crhr2−/− mice show altered feeding responses to Ucn.
Figure 5: Ucn increases cardiac function in wild-type but not Crhr2−/− mice.

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Acknowledgements

We thank K. Lee and A. Contarino for discussing relevant and unpublished data; and J. Auld, W. Yeung and Q. Yue for assistance. This work was supported by National Institute of Health grants HL55512 (M.P.S.-P.), HL45043 (A.R.H.), HD30236 (M.J.L.), 2T32EY07123 (K.A.H.), AI14985 (M.B.R.) and an American Heart Association Fellowship (S.C.C.).

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Author notes

  1. Sarah C. Coste and Robert A. Kesterson: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, Oregon, USA

    Sarah C. Coste, Kurt A. Heldwein, Susan L. Stevens, Amanda D. Heard, Jacob H. Hollis, Susan E. Murray, Jennifer K. Hill, Marvin B. Rittenberg & Mary P. Stenzel-Poore

  2. Departments of Medicine, Oregon Health Sciences University, Portland, Oregon, USA

    George A. Pantely

  3. Departments of Obstetrics and Physiology, Oregon Health Sciences University, Portland, Oregon, USA

    Alan R. Hohimer

  4. Departments of Behavioral Neuroscience, Oregon Health Sciences University, Portland, Oregon, USA

    Daniel C. Hatton, Tamara J. Phillips & Deborah A. Finn

  5. Departments of Pathology, Oregon Health Sciences University, Portland, Oregon, USA

    Peter Stenzel

  6. Departments of Vollum Institute, Oregon Health Sciences University, Portland, Oregon, USA

    Malcolm J. Low

  7. Departments of Congenital Heart Research Center, Oregon Health Sciences University, Portland, Oregon, USA

    George A. Pantely, Alan R. Hohimer, Daniel C. Hatton, Peter Stenzel & Mary P. Stenzel-Poore

  8. Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Robert A. Kesterson

  9. Department of Veterans Affairs Medical Center, Portland, Oregon, USA

    Tamara J. Phillips

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  1. Sarah C. Coste
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Corresponding author

Correspondence to Mary P. Stenzel-Poore.

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Coste, S., Kesterson, R., Heldwein, K. et al. Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nat Genet 24, 403–409 (2000). https://doi.org/10.1038/74255

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