Prenatal cold‐induced sympathetic stress programs long‐term cardiac β‐adrenergic dysregulation and metabolic impairment in female rat offspring

Abstract Gestational cold‐induced sympathetic stress increases maternal norepinephrine (NE) release, thereby altering the fetal environment and enhancing fetal NE exposure. This prenatal insult contributes to developmental programming, leading to long‐term cardiovascular alterations. While most studies have focused on male offspring, we investigated the impact of gestational cold‐induced sympathetic stress on cardiovascular and metabolic outcomes in female progeny. Pregnant Sprague–Dawley rats were exposed to intermittent cold stress without hypothermia (4°C for 3 h daily), and their female offspring were evaluated at postnatal days 20 and 60. Hearts were analyzed for β‐adrenergic receptor (βAR) mRNA expression, protein abundance, receptor binding affinity, and NE concentration. In addition, in vivo glucose tolerance and cardiovascular responses to isoproterenol (ISO) were assessed. Stressed female offspring showed increased ventricular weight at 20 and 60 days without significant changes in cardiac NE content. β 1 AR mRNA levels were elevated at day 20 in the stressed group, but not at day 60. β 2 AR mRNA expression was also increased at day 20, and the β 1 /β 2 receptor ratio was higher at day 20. Radioligand binding revealed reduced βAR affinity at day 60, despite unaltered receptor density. ISO treatment in vivo led to 40% mortality by the third day in stressed females without mortality in control female offspring. Metabolically, adult female offspring displayed glucose intolerance and compensatory hyperinsulinemia, consistent with insulin resistance. These results indicate that prenatal cold‐induced sympathetic stress induces long‐lasting alterations in cardiac β‐adrenergic signaling and metabolic regulation in female offspring, highlighting a vulnerability to cardiometabolic dysfunction.