BRAIN PERIVASCULAR MACROPHAGES CONTRIBUTE TO THE DEVELOPMENT OF HYPERTENSION THROUGH SYMPATHETIC ACTIVATION IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

Abstract

Objective: 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 contribute to sympathoexcitaion in a heart failure model. We thus investigated whether brain PVMs contribute to the development of hypertension through sympathoexcitation. Design and method: We measured blood pressure and evaluated the number of brain PVMs and the plasma levels of proinflammatory cytokines in stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar–Kyoto rats (WKY) at the ages of 4, 8, and 12 weeks. To determine the contribution of brain PVMs to blood pressure elevation, we intracerebroventricularly injected liposome-encapsulated clodronate, which eliminates macrophages by inducing apoptosis, or vehicle into 8-week-old SHRSP and WKY; we then assessed its effects in 10-week-old rats. We also investigated the effects of clodronate treatment on responses to the acute intravenous injection of proinflammatory cytokines in WKY. Results: SHRSP developed hypertension over 8 weeks 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 WKY. Clodronate treatment attenuated the increase in blood pressure in SHRSP (δmean blood pressure, 11.6 ± 3.8 mmHg vs. 23.8 ± 1.9 mmHg; clodronate vs. vehicle, n = 7, p < 0.05) but not in WKY. Clodronate treatment reduced the depressor effect of hexamethonium, an index of sympathetic activity; it also reduced the neuronal activity marker c-Fos 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 (RSNA) in response to an acute intravenous injection of interleukin-1β in WKY (δmean blood pressure, 8.8 ± 2.5 mmHg vs. 21.2 ± 4.6 mmHg; integrated RSNA, 125.6 ± 10.4 % vs. 213.1 ± 22.2 %; clodronate vs vehicle, n = 5, p < 0.05). Conclusions: Brain PVMs contribute to the development of hypertension via sympathetic activation. PVMs may be activated by increased levels of circulating interleukin-1β.