Abstract 104: Cerebrovascular and Cognitive Dysfunction in DOCA-Salt Hypertension is Mediated by Perivascular Macrophages

Abstract

Hypertension (HTN) and high-salt diets are important risk factors for stroke and dementia. DOCA-salt is a recognized model of HTN driven by sodium retention and brain renin-angiotensin system (RAS) activation. However, it is unknown whether essential mechanisms regulating the cerebral circulation are altered in DOCA-salt mice, and, if so, whether these alterations are associated with cognitive impairment. To this end, C57BL/6 mice were implanted with 50mg DOCA pellets SQ and received 0.9% NaCl drinking water for 3 weeks. Cerebral blood flow (CBF) was measured in the somatosensory cortex by laser-Doppler flowmetry through a cranial window. DOCA-salt increased systolic blood pressure (BP; 148±3 vs 112±3 mmHg in controls; p<0.01), and attenuated the CBF increase induced by whisker stimulation (WS; 16.0±1.1 vs 22.4±0.6 %; p<0.01) or by cortical application of acetylcholine (ACh; 13.5±0.9 vs 22.8±1.1 %; p<0.01), without affecting the response to the smooth muscle relaxant adenosine. Cerebrovascular dysfunction was associated with cognitive impairment as assessed by Novel Object Recognition and Barnes Maze tasks (p<0.01). Perivascular macrophages (PVM) express AT1R and Nox2, and, as such, may be a key source of radicals mediating the cerebrovascular effects of brain RAS overactivity. To test this hypothesis, brain PVM were depleted by icv administration of clodronate (CLO) liposomes. BP was not affected by CLO in either control or DOCA mice (p>0.05). PVM depletion improved novel object exploration (p<0.01) and time spent in the target quadrant of Barnes Maze (p<0.05), while also restoring the CBF responses to both WS (DOCA-CLO 19.6±0.9%; p<0.05) and ACh (DOCA-CLO 20.0±1.7%; p<0.05). Next, we tested whether reactive oxygen species (ROS) are involved in the cerebrovascular dysfunction. We observed a 45% upregulation in gp91 mRNA in cerebral vessels from DOCA mice, which was prevented by PVM depletion (p<0.05). Application of the ROS scavenger MnTBAP rescued CBF responses to both WS (20.3±0.9%; p<0.05) and ACh (19.0±0.8%; p<0.05) in DOCA-salt HTN. We conclude that PVM play a previously unrecognized role in the cerebrovascular and cognitive dysfunction of DOCA-salt HTN and may represent a new therapeutic target to alleviate the neurocognitive effects of HTN.