Prefrontal-medullary Circuitry Impacts Sex-specific Microvascular Function Following Chronic Stress

Abstract

Vascular dysfunction is a prominent factor underlying cardiovascular disease, the leading cause of death worldwide. Additionally, chronic stress contributes to cardiovascular pathologies in a sex-dependent manner. However, the neurobiological mechanisms mediating the sex-specific impact of chronic stress on vascular function are not known. Our previous studies found that the prefrontal infralimbic cortex (IL)-rostral ventrolateral medulla (RVLM) circuit inhibits sympathetic and endocrine responses to stress; therefore, the current study tested the hypothesis that the IL-RVLM circuit is necessary to mitigate microvascular dysfunction following chronic stress. To this end, an intersectional genetic approach was used to induce Cre-dependent expression of tetanus toxin light chain and inhibit neurotransmitter release from RVLM-projecting IL neurons in male and female rats. Rats were then exposed to 2 weeks of chronic variable stress (CVS) or remained unstressed. Left ventricle structure was assessed by echocardiography and microvascular function was subsequently assessed by resistance arteriole pressure myography. Arteriole myogenic tone, endothelial-independent vasoconstriction, as well as endothelial-dependent vasodilation and vasoconstriction were determined at both normotensive (70 mmHg) and hypertensive (120 mmHg) pressures. Our results indicate that heart size and ventricular thickness were impacted in a sex-dependent manner. Circuit inhibition increased heart index in females regardless of stress. In males, circuit inhibition reduced ventricular wall thickness in diastole. Microvasculature also exhibited sex-dependent function. Following CVS, males had increased myogenic tone compared to females. Circuit inhibition also differentially impacted vasodilation in males and females. In chronically stressed females, circuit inhibition increased endothelial-dependent vasodilation at both normotensive and hypertensive pressures and normotensive endothelial-independent relaxation. These changes indicate that chronic stress leads to female microvascular dysfunction that is exacerbated by IL-RVLM inhibition. Chronically stressed males had no changes in normotensive vasodilation. However, with elevated pressure, circuit-inhibited CVS males had increased endothelial-dependent vasodilation. In contrast, unstressed males with circuit inhibition had decreased endothelial-dependent vasodilation at 120 mmHg, indicating that the male IL-RVLM circuit may be necessary for vascular function during acute hypertensive events. Broadly, these results support the hypothesis that the IL-RVLM circuit is necessary for appropriate vascular function and that circuit inhibition and chronic stress lead to sex-specific responses that may differentially impact the progression of cardiovascular disease. NIH R01 HL150559 (B.Myers) NIH F30 OD032120 (C. Dearing). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.