750.3 - Angiotensin II Type 1 Receptor-Mediated Hypothalamic Paraventricular Nucleus Neuroinflammation And Blood Brain Barrier Disruption Contribute To Age-Dependent Hypertension In Male, But Not Female, Sprague Dawley Rats
Presenting Author Boston University School of Medicine
Aim: Aging is a risk factor for the development of hypertension. Recently, neuroinflammation in cardio-regulatory centers of the brain, specifically the hypothalamic paraventricular nucleus (PVN), has been identified as a potential driver of hypertension via sympathetically-mediated mechanisms. We hypothesize neuroinflammatory mechanisms contribute to the progression of age-dependent hypertension.
Methods: In male (M) Sprague Dawley (SD) rats aged 3, 8, and 16 months old (MO) and female (F) SD rats aged 3 and 16 MO femoral artery cannulation was used to measure mean arterial pressure (MAP; mmHg) and assess sympathetic tone to the vasculature (ΔMAP; mmHg) via depressor response to ganglionic blockade (i.v. hexamethonium 30 mg/kg). Global sympathetic tone was assessed as plasma norepinephrine (nmol/L) via ELISA. Blood brain barrier (BBB) dysfunction in the PVN was assessed via PVN FITC extravasation following co-infusion of FITC-Dextran (10 kDa) and rhodamine B isothiocyanate-Dextran (70 kDa). Immunohistochemistry was performed in male rats only for microglia (CD11b/c), astrocytes (GFAP), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the PVN. MAP, assessments of sympathetic tone, BBB dysfunction, and microglia and astrocyte activity were also measured in 16 MO M rats treated with subcutaneous (s.c.) losartan, an Angiotensin II Type 1 Receptor (AT1R) antagonist, for 21 days (s.c. 3 mg/kg/day; Nf6/group).
Results: M, but not F, SD rats develop age-dependent hypertension (MAP [mmHg] 3 MO M 124±4, 8 MO M 138±5, 16 MO M 153±5, plt;0.05; 3 MO F 132±5, 16 MO F 133±4), increased vascular sympathetic tone (ΔMAP to hexamethonium [mmHg] 3 MO M -34±7, 8 MO M -68±5, 16 MO M -60±9, plt;0.05; 3 MO F -36±8, 16 MO F -34±8) and increased global sympathetic tone (Plasma NE [nmol/L] 3 MO M 39±6, 8 MO M 44±8, 16 MO M 58±9, plt;0.05; 3 MO F 44±6, 16 MO F 46±7). In M rats only, BBB dysfunction occurs at 8 MO and 16 MO- F rats do not exhibit BBB disruption with age (% FITC extravasation [% area] 3 MO M 1.5±1.0, 8 MO M 9.4±1.3, 16 MO M 9.8±2.6, plt;0.05; 3 MO F 1.3±0.6, 16 MO F 2.67±1.37). Further, 16 MO M rats exhibit significant neuroinflammation indicated by increased astrocyte reactivity and microglial activation, and increased IL-6 and TNF-α expression in the PVN. Following losartan administration in 16 MO M rats, there is a significant decrease in MAP, vascular and global sympathetic tone. BBB disruption is attenuated and neuroinflammation is ameliorated following losartan treatment as shown by a decrease in microglial activation and astrocytic reactivity.
Conclusions: Age-dependent hypertension develops in a sex-dependent manner in the SD rat, potentially due to a protective effect of female sex steroids. Amelioration of neuroinflammation and reduction of BBB disruption via AT1R antagonism attenuates hypertension, vascular tone and global sympathetic outflow in an age-dependent manner in male rats. These results indicate that PVN neuroinflammation modulates sympathetic nervous system activity and age-related control of blood pressure in male rats potentially by an AT1R-mediated mechanism.
Funding for this project was provided by NIH R01 AG062515 to R.D.W.
