Brainstem glial senescence and dysfunction in obesity-induced hypertension

Elevated sympathetic nerve activity (SNA) mediates the increased risk for hypertension and heart failure in obesity. Yet the mechanisms that contribute to obesity-induced increases in SNA remain unclear. Our lab has previously demonstrated a critical role for oxidative stress in the RVLM, a key brainstem region that regulates sympathetic outflow, in obesity-induced sympathetic overactivity. Although RVLM neurons responsible for sympathetic control of cardiovascular activities have been studied extensively, little or no attention has been paid to their non-neuronal neighbours, astrocytes and microglia. Exciting preliminary studies from our lab suggest that astrocytes and microglia in the RVLM display distinct phenotypical changes in response to chronic oxidative stress in obesity. We provide novel evidence that microglia in the RVLM are most vulnerable to undergo senescence, a stress response that significantly alters cellular phenotypes and potentially contributes to inflammation through senescence-associated secretory phenotype (SASP). On the other hand, obesity impairs astrocytic glutamate reuptake transporter activity (EAAT2) and enhances extrasynaptic glutamate excitatory tone in the RVLM. In addition to these cell-autonomous mechanisms, our exciting preliminary studies indicate that soluble factors secreted from senescent microglia negatively regulate astrocytic EAAT2 expression, indicating potential crosstalk between senescent microglia and astrocytes in the RVLM as another likely mechanism for obesity-induced sympathoexcitation and hypertension. Guided by strong preliminary data and published studies, we will test the following hypothesis that obesity causes glial dysfunction in the RVLM marked by microglial senescence and impaired astrocytic glutamate reuptake transporter activity. The resulting neuroinflammation and increased glutamate excitatory tone in the RVLM contribute to increases in blood pressure and SNA in obesity. In aim 1, we will determine the mechanistic role of senescent microglial cells and their secretory phenotype on SNS overactivity and hypertension in obesity. In aim 2, we will determine the mechanism by which astrocytic dysfunction in the RVLM contributes to sympathoexcitation and hypertension in obesity. In aim 3, we will determine the role of microglia-astrocyte interaction in obesity-induced sympathoexcitation. We will use an array of novel transgenic mice models (targeted senescence induction and elimination), cell-type-specific gene delivery techniques, state-of-the-art radiotelemetry for continuous monitoring of cardiovascular parameters in conscious mice, cutting-edge proteomics, lipidomics and single-cell sequencing approaches to accomplish the proposed aims. Overall, our studies will shed light on the often-overlooked glial mechanisms and offer new therapeutic targets (senolytics and EAAT2 activators) for the prevention or treatment of hypertension in obese individuals