Microglial SHIP1 contributes to inflammation-driven hemodynamic responses and sympathetic outflow

Inflammation is implicated in pathophysiology in cardiovascular diseases including hypertension and heart failure. Proinflammatory cytokines (PICs) in the brain substantially elevate blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA), suggesting that PICs-driven neuroinflammation plays a critical role in the regulation of cardiovascular function and sympathetic outflow. We recently identified that Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) is selectively expressed in microglia, particularly within the hypothalamic paraventricular nucleus, a critical cardiovascular/autonomic brain region. SHIP1 is an important signaling molecule regulating PI3K/Akt-mediated NLRP3 inflammasome activation and interleukin (IL)-1β and IL-18 production. However, its role in regulating hemodynamic responses and sympathetic activity remains unclear. Using electrophysiological recording technique, we examined the effects of SHIP1 on BP, HR, and RSNA under inflammatory conditions-induced by intravenous lipopolysaccharide (LPS, 20 mg/kg) in urethane-anesthetized male SD rats. Mean BP (MBP, mmHg), HR (beats/min), and RSNA (% change from baseline) were recorded continuously over 4-5 hours, with SHIP1 activator (AQX-1125) or inhibitor (3AC) administered intracerebroventricularly (ICV). Our results indicated that ICV 3AC significantly (*p<0.01) increased MBP (11.7 ± 9.1*), HR (76.9 ± 2.8*), and RSNA (64.6 ± 9.8*), with effects observed 20–30 minutes post-injection. Conversely, pretreatment with ICV SHIP1 activator AQX-1125 markedly attenuated LPS-induced increase (* p<0.01, LPS vs. LPS+AQX-1125) in MBP (23.7 ± 3.7* to 11.8 ± 5.2*), HR (135.6 ± 2.1* to 55.4 ± 1.3*), and RSNA (118.4 ± 4.7* to 92.2 ± 2.5*). These findings demonstrate that SHIP1 in the brain is a critical negative regulator of inflammation-driven hemodynamic responses and sympathetic overactivity. Targeting SHIP1 may provide a novel therapeutic approach for managing neuroinflammation-associated cardiovascular dysfunction in hypertension and heart failure. Supported by R01 HL-139521 and HL-155091 (to Dr Wei) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.