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Brain perivascular macrophages contribute to the development of hypertension in stroke-prone spontaneously hypertensive rats via sympathetic activation

Hypertension Research volume 43, pages 99–110 (2020)Cite this article

Abstract

Hypertension is associated with systemic inflammation. The activation of the sympathetic nervous system is critically involved in the pathogenesis of hypertension. Brain perivascular macrophages (PVMs) can be affected by circulating inflammatory cytokines, and the contribution of brain PVMs to sympathoexcitation has been demonstrated in a heart failure model. We thus investigated whether brain PVMs contribute to the development of hypertension through sympathoexcitation. Stroke-prone spontaneously hypertensive rats (SHRSP) developed hypertension over an 8-week period from 4 to 12 weeks of age. The number of brain PVMs and plasma interleukin-1β levels significantly increased at the ages of 8 and 12 weeks in SHRSP compared with normotensive Wistar–Kyoto rats (WKY). To determine the contribution of brain PVMs to blood pressure elevation, we intracerebroventricularly injected liposome-encapsulated clodronate, which eliminates macrophages by inducing apoptosis, into 8-week-old rats; we then assessed its effects in 10-week-old rats. Clodronate treatment attenuated the increase in mean blood pressure in SHRSP but not in WKY. Clodronate treatment reduced the depressor effect of hexamethonium, an index of sympathetic activity; it also reduced neuronal activity in sympathetic regulatory nuclei such as the hypothalamic paraventricular nucleus and rostral ventrolateral medulla and reduced the expression of cyclooxygenase-2 and prostaglandin E2, a downstream pathway in activated macrophages, in SHRSP but not in WKY. Furthermore, clodronate treatment attenuated the increase in blood pressure and renal sympathetic nerve activity in response to an acute intravenous injection of interleukin-1β in WKY. In conclusion, brain PVMs contribute to the development of hypertension via sympathetic activation. PVMs may be activated by increased levels of circulating interleukin-1β.

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Acknowledgements

This work was supported by JSPS Grants-in-Aid for Scientific Research Grant numbers JP17K16012 and JP17K09508.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan

    Takeshi Iyonaga, Keisuke Shinohara, Taku Mastuura & Hiroyuki Tsutsui

  2. International University of Health and Welfare, Fukuoka, Japan

    Yoshitaka Hirooka

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Correspondence to Keisuke Shinohara.

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HT received honoraria from Daiichi Sankyo, Inc., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Boehringer Ingelheim Japan, Inc., Novartis Pharma K.K., Bayer Yakuhin, Ltd., Bristol-Myers Squibb K.K., and Astellas Pharma Inc. and research funding from Actelion Pharmaceuticals Japan, Daiichi Sankyo, Inc., and Astellas Pharma Inc. All other authors declare that they have no conflict of interest.

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Iyonaga, T., Shinohara, K., Mastuura, T. et al. Brain perivascular macrophages contribute to the development of hypertension in stroke-prone spontaneously hypertensive rats via sympathetic activation. Hypertens Res 43, 99–110 (2020). https://doi.org/10.1038/s41440-019-0333-4

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