Early life stress induces vascular dysfunction and aortic stiffness mediated by adrenergic signaling in male and female mice

Early Life Stress (ELS) is experienced by two thirds of the United States population and is a risk factor for the development of cardiovascular disease. Previous work from our lab has demonstrated that exposure to early life stress results in vascular dysfunction and increased vascular stiffness as early as adolescence. One of the primary pathways by which stress, as perceived by the central nervous system, is translated to whole body pathologies is the catecholamine/adrenergic receptor pathways. In chronic stress, overstimulation of beta-2 adrenergic receptors results in maladaptive signaling which results in vascular dysfunction. However, very little is known about adrenergic signaling in the vasculature in ELS. We hypothesized that chronic exposure to catecholamines during critical periods of early life leads to aberrant signaling of adrenergic receptors later in life resulting in impaired vascular function and stiffer vessels. Utilizing the maternal separation with early weaning (MSEW) murine model of ELS, we first investigated the response of the aorta and kidney afferent arterioles to alpha adrenergic agonist phenylephrine (PE). Wire myography with aortic rings of MSEW and normally reared (NR) male mice revealed a blunted response of MSEW aortas to PE (NR: Emax=85.05%+/-6.25, MSEW Emax=64.04%+/-7.36, p=0.047, n=11,7). Furthermore, using juxtamedullary nephron preparations showed impaired response to PE in afferent arterioles in the kidney from male MSEW mice as compared to NR (NR: EC50(LogM)= 1.7*e-7+/-1.9e-8, MSEW: EC50(LogM)=9.1*e-7+/-1.8e-8, p=0.0039, n=5). Together, these findings suggest aberrant response to catecholamine stimulation in large conduit and kidney resistance arteries. Next, we treated male and female MSEW and NR mice with beta-2 adrenergic receptor inverse agonist ICI 118,551 HCl (2mg/kg) for 10 days starting at 10 weeks of age. Pulse wave velocity (PWV) was measured before and after treatment and tissues were collected for histology at 12 weeks. Prior to treatment, MSEW has significantly elevated PWV as compared to NR in both male and female mice (m/sec; male: NR: 1.42+/-0.07, MSEW: 2.14+/-0.09 P=0.0003 n=3,10; female: NR 1.76+/-0.12, MSEW: 2.24+/-0.08, P=0.0002, n=8,11). After treatment, no significant difference was found with PWV from treated MSEW and NR in male and female mice (m/sec; male: NR: 1.46+/-0.07, MSEW: 1.64+/-0.09, n=3,10; female: NR; 1.76+/-0.11, MSEW:1.82+/-0.12, n=8,11). These findings suggest reducing activity of beta 2 adrenoreceptors ameliorates ELS-induced vascular stiffness. Verhoeff Van Gieson (EVG) staining of elastin in the aorta demonstrated a trending increase in the percentage of elastin following treatment with ICI 118,551 HCl in MSEW mice as compared to vehicle (Elastin as % tunica media area; MSEW Vehicle: 24.9%+/-0.02, MSEW ICI 118,551 HCl 32.4%+/-0.02, n=4, P=0.05). Overall, these findings indicate that ELS induced vascular dysfunction is mediated through catecholamine signaling via adrenergic receptors. Beta-blockers are readily used in clinical settings, therefore, establishing a connection between catecholamines and ELS-induced vascular dysfunction provides a potential therapeutic target to mitigate the cardiovascular health impacts of ELS. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.