Brain perivascular macrophages contribute to the development of hypertension in stroke-prone spontaneously hypertensive rats via sympathetic activation
Brain perivascular macrophages contribute to the development of hypertension in stroke-prone spontaneously hypertensive rats via sympathetic activation
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DOI：
10.1038/s41440-019-0333-4
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发表时间：
2020-02-01
影响因子：
5.4
通讯作者：
Tsutsui, Hiroyuki
中科院分区：
文献类型：
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作者：
Iyonaga, Takeshi;Shinohara, Keisuke;Tsutsui, Hiroyuki
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关键作用。脑血管周围巨噬细胞（PVM）可受到循环炎性细胞因子的影响，并且脑PVM对交感神经兴奋的贡献已在心力衰竭模型中得到证实。因此，我们研究了脑PVM是否通过交感神经兴奋促进高血压的发展。易卒中的自发性高血压大鼠（SHRSP）在4至12周龄的8周内发生高血压。与血压正常的Wistar-Kyoto大鼠（WKY）相比，SHRSP的脑PVM数量和血浆IL-1 β水平在8和12周龄时显著增加。为了确定脑PVM对血压升高的贡献，我们向8周龄大鼠脑室内注射脂质体包封的氯膦酸二钠，其通过诱导细胞凋亡消除巨噬细胞;然后我们评估其在10周龄大鼠中的作用。氯膦酸盐治疗减弱了SHRSP的平均血压升高，但在WKY中没有。氯膦酸盐治疗降低了六甲双铵的降压作用，交感神经活性的指数，它也减少了交感神经调节核，如下丘脑室旁核和延髓头端腹外侧区的神经元活动，并减少了环氧合酶-2和前列腺素E2的表达，在激活的巨噬细胞的下游途径，在SHRSP，但不是在WKY。此外，氯膦酸盐治疗减弱了WKY患者急性静脉注射白细胞介素-1 β后血压和肾交感神经活动的增加。总之，脑PVM通过交感神经激活促进高血压的发展。PVM可能被循环白细胞介素-1 β水平升高激活。
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-1 beta 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-1 beta 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-1 beta.