Aging Alters Cerebrovascular Endothelial GPCR and K⁺ Channel Function: Divergent Role of Biological Sex

Age-related dementia entails impaired blood flow to and throughout the brain due, in part, to reduced endothelial nitric oxide signaling. However, it is unknown whether sex affects cerebrovascular G_q-protein-coupled receptors (GPCRs) and K+ channels underlying endothelium-derived hyperpolarization (EDH) during progressive aging. Thus, we simultaneously evaluated intracellular Ca²⁺ ([Ca²⁺]_i) and membrane potential (V_m) of intact endothelial tubes freshly isolated from posterior cerebral arteries of young (4–6 mo), middle-aged (12–16 mo), and old (24–28 mo) male and female C57BL/6 mice. Purinergic receptor function (vs. muscarinic) was dominant and enhanced for [Ca²⁺]_i increases in old females versus old males. However, Ca²⁺-sensitive K+ channel function as defined by NS309-evoked V_m hyperpolarization was mildly impaired in females versus males during old age. This sex-based contrast in declined function of GPCRs and K+ channels to produce EDH may support a greater ability for physiological endothelial GPCR function to maintain optimal cerebral blood flow in females versus males during old age. As reflective of the pattern of cerebral blood flow decline in human subjects, inward-rectifying K⁺ (K_IR) channel function decreased with progressive age regardless of sex. Combined age-related analyses masked male versus female aging and, contrary to expectation, hydrogen peroxide played a minimal role. Altogether, we conclude a sex-based divergence in cerebrovascular endothelial GPCR and K+ channel function while highlighting a previously unidentified form of age-related endothelial dysfunction as reduced K_IR channel function.