Blood brain barrier dysfunction and a role for inflammation in age-dependent salt-sensitive hypertension
Nist, Kayla Marie
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Hypertension is the principal risk factor for chronic kidney disease, myocardial infarction, and stroke, and is responsible for 10% of deaths globally. Normal aging and elevated dietary sodium intake have both been identified as contributors to hypertension, the salt sensitivity of blood pressure, and elevations in sympathetic tone. Normal aging has also been identified as a contributor to vascular dysfunction and inflammation. We hypothesize that normal aging and increased dietary sodium intake contribute to the development and maintenance of age-related salt-sensitive hypertension. We anticipate with age that there are elevations in sympathetic tone, decreases in the vascular integrity of the blood brain barrier, and an increase in the inflammatory response of the innate immune system of the brain by astrocytes and microglia. Using male Sprague-Dawley (SD) rats aged 3-, 8- and 16-months-old as a model of normal aging, rodents were randomly assigned to a normal salt (NS; 0.6% NaCl) or high salt (HS; 4% NaCl) diet. We then assessed the development of hypertension, the salt sensitivity of blood pressure, changes in central vascular integrity, and a role for central inflammation in age-dependent hypertension. We observed a robust age-dependent increase in blood pressure in rodents on a NS diet suggesting male SD rats develop age-dependent hypertension. We also observed that aged rats develop the salt sensitivity of blood pressure. We saw significant elevations in global sympathetic tone, sympathetic tone to the vasculature, and sympathetic tone to the kidney in response to normal aging. Further, there was a dramatic extravasation of intravascularly infused dextrans in the paraventricular nucleus of the hypothalamus (PVN) with age, suggesting a loss in vascular integrity of the blood brain barrier, regardless of dietary sodium intake. Astrocytic density in the PVN was maintained in animals on a NS diet. In rodents on a HS diet, both young and middle aged rats, but not in aged rats showed increased levels of astrocytic density. There was no difference in interstitial astrocyte densities, which excluded perivascular astrocytes, compared to total astrocyte density, suggesting that perivascular astrocytes did not play a significant role in astrocyte activation. Microglial branching complexity was maintained in all groups regardless of salt intake, suggesting that microglial activation was the same through all groups. However, microglial morphology showed a trending increase in activation level on a NS with age. On a HS diet, there is an increase in activation state at 8-months-old. Overall, normal aging and increases in dietary sodium intake contribute to increases in blood pressure, elevations in sympathetic tone, and ultimately a loss in vascular integrity of the blood brain barrier. Importantly, the following studies reveal a novel breakdown in the blood brain barrier in a normal aging model of hypertension by which increased blood pressure and aging evokes an increase in blood brain barrier permeability.