Brain Perivascular Macrophages Contribute to Developing Hypertension via Sensing Chronic Peripheral Inflammation

Abstract

BackgroundRecent studies suggest an association between inflammation and hypertension. The essential pathophysiological mechanism by which peripheral inflammation induces sympathetic hyperactivity and blood pressure elevation is not fully clarified. Sympathetic nerve activity is regulated by the brain, which is separated from various peripheral substances by the blood brain barrier (BBB). Brain perivascular macrophages in the BBB can transfer peripheral inflammatory information to the brain. Therefore, we investigated whether peripheral proinflammatory cytokines accompany the development of hypertension, and if so, whether or not brain perivascular macrophage depletion attenuates the increase in blood pressure in hypertensive animal models.Methods and ResultsPeripheral proinflammatory interleukin‐6 levels measured by enzyme‐linked immunosorbent assay did not differ between young pre‐hypertensive spontaneously hypertensive rats (SHR) and control Wistar Kyoto rats (WKY, 8‐week‐old SHR 64.8±9.5 pg/ml vs. 8‐week‐old WKY 42.8±9.5 pg/ml, p=0.15, respectively, n=4 for each). In adult hypertensive SHR, however, the interleukin‐6 level was significantly greater than that in WKY (12‐week‐old SHR 112.5±15.2 pg/ml vs. 12‐week‐old WKY 62.4±15.2 pg/ml, p<0.05, n=5 for each). Clodronate, a unique agent that induces apoptosis of perivascular macrophages, was administered intracerebroventricularly to 6‐week‐old SHR to investigate the role of brain perivascular macrophages in blood pressure elevation in SHR. Although established natural history of blood pressure in SHR clearly showed that mean arterial pressure would be elevated to approximately 120–125 mmHg at 8 weeks of age, intracerebrovantricular injection of clodronate successfully attenuated telemetered mean blood pressure elevation from 6 to 8 weeks of age (from 113.3±4.2 mmHg to 114.7±4.2 mmHg, n=2) in SHR.ConclusionBrain perivascular macrophages potentially contribute to developing hypertension via sensing chronic peripheral inflammation.