Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
International University of Health and Welfare, Fukuoka, Japan.
Hypertens Res. 2020 Feb;43(2):99-110. doi: 10.1038/s41440-019-0333-4. Epub 2019 Sep 20.
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.
高血压与全身炎症有关。交感神经系统的激活在高血压的发病机制中起着至关重要的作用。脑周细胞巨噬细胞（PVMs）可以受到循环炎症细胞因子的影响，并且在心力衰竭模型中已经证明脑 PVMs 对交感神经兴奋有贡献。因此，我们研究了脑 PVMs 是否通过交感神经兴奋导致高血压的发展。易发生中风的自发性高血压大鼠（SHRSP）在从 4 至 12 周龄的 8 周期间发展为高血压。与正常血压的 Wistar-Kyoto 大鼠（WKY）相比，8 周和 12 周龄 SHRSP 中脑 PVMs 的数量和血浆白细胞介素-1β水平显著增加。为了确定脑 PVMs 对血压升高的贡献，我们将包封在脂质体中的氯膦酸盐注入 8 周龄大鼠的侧脑室；然后在 10 周龄大鼠中评估其效果。氯膦酸盐处理可减轻 SHRSP 血压升高，但对 WKY 无影响。氯膦酸盐处理降低了交感神经活性指标六烃季铵的降压作用；它还降低了下丘脑室旁核和延髓头侧腹外侧区等交感调节核的神经元活性，并降低了 SHRSP 中环氧合酶-2 和前列腺素 E2 的表达，这是激活的巨噬细胞中的下游途径，但对 WKY 无影响。此外，氯膦酸盐处理可减轻 WKY 中白细胞介素-1β急性静脉注射引起的血压和肾交感神经活动的增加。总之，脑 PVMs 通过交感神经激活导致高血压的发展。PVMs 可能被循环白细胞介素-1β水平的增加激活。
