Abstract 041: Impaired Meningeal Lymphatic Drainage and Cognition in DOCA-salt Hypertension

The meningeal lymphatic system promotes clearance of cerebrospinal fluid (CSF) to maintain central nervous system (CNS) homeostasis. In aging and neurodegeneration, meningeal lymphatic function is impaired, promoting buildup of toxic proteins in the CNS and driving cognitive impairment. We have previously shown an enhanced meningeal immune response during deoxycorticosterone acetate (DOCA)-salt hypertension, contributing to impairment of neurovascular coupling and cognitive function. However, the relationship between the meningeal lymphatics, meningeal immunity, and the deleterious cognitive effects of hypertension has not been fully elucidated. We tested the hypothesis that DOCA-salt hypertension impairs CSF drainage via the meningeal lymphatic system. 3-month-old C57BL/6 male mice were implanted with a s.c. DOCA pellet and received 0.9% NaCl drinking water for 21 days; control mice received a sham surgery (n=10/group). Blood pressure was monitored by tail-cuff plethysmography. Lymphatic vessels were assessed by immunohistochemistry using the lymphatic vessel marker LYVE1. DOCA-salt mice developed increased systolic blood pressure (control: 112.7 ± 3.5 vs DOCA: 135.9 ± 11.4 mmHg; p=0.0002). DOCA-salt mice also showed an increase in LYVE1+ area surrounding the dural sinuses (control: 4.098 ± 1.411 vs DOCA: 6.431 ± 1.984 %CD31 sinus area; p=0.0110). In a separate group of DOCA-salt and control mice, we delivered Alexa647-ovalbumin (OVA-647) via either intra-cisterna magna (i.c.m) or striatal injection to assess clearance of CSF vs parenchymal macromolecules. We observed impaired CSF drainage into the superficial cLNs in DOCA-salt mice administered i.c.m. OVA-647 (control: 15.22 vs DOCA: 0.7840 a.u.; p0.05), suggesting unaltered clearance across the blood-brain barrier or perivascular pathways. These data suggest impaired clearance of CSF macromolecules despite structural expansion of meningeal lymphatic vessels during DOCA-salt hypertension. Ongoing studies will assess the interaction between meningeal lymphatics and dural immunity in hypertension. Impairment of CSF drainage mechanisms alters clearance of CNS waste and thus may contribute to cognitive decline in hypertension.