Psychosocial stress-induced neurometabolic dysfunction as a mediator ofpostpartum cardiovascular disease

In the United States, cardiovascular events and neuropsychiatric disorders are the two leading non-obstetric causes of maternal mortality. Postpartum cardiovascular disease affects 10-26% of patients and encompasses myocardial infarction, cardiomyopathy, coronary artery disease, and hypertension. Postpartum depression (PPD) is a postpartum neuropsychiatric disorder that affects up to 22% of mothers and consists of a major depressive episode. Cardiovascular disease and PPD are highly comorbid and significantly impacted by psychosocial stress. This relationship is particularly evident in the postpartum period where PPD patients exhibit a 70% increased risk of developing cardiovascular disease in the 5 years after delivery. The clear bidirectional relationship between these two conditions points to a neurogenic mechanism induced by stress, but the effects of social stress on cardiovascular disease and PPD in the postpartum are unclear. Witness Stress is a psychosocial stressor that induces robust cardiac and behavioral effects in virgin females, however our knowledge of effects in postpartum females is scarce. Mitochondria are emerging as key players in health and disease, yet little is known about postpartum mitochondrial function. To address these critical knowledge gaps, we propose to delineate the neurogenic mechanisms underlying witness stress-induced postpartum cardiac stress and PPD phenotypes. Our central hypothesis, founded on published and preliminary data is that psychosocial stress-evoked mitochondrial dysfunction in glutamatergic cells in the mPFC directly contributes to shifts in postpartum cardiovascular and biobehavioral function. We will test this hypothesis using female rats in two specific aims. Aim 1 will determine if direct mPFC mitochondrial stabilization during witness stress is sufficient to prevent postpartum cardiovascular and behavioral dysfunction. Aim 2 will determine if indirect mitochondrial stabilization via inhibition of microglial activation prevents stress-evoked outcomes. The proposed research is significant because results will reveal neurogenic mechanisms linked to systemic pathologies. Moreover, our findings will increase knowledge on an understudied critical sex-linked health period following exposure to a gender-relevant social stressor and identify potential preventative treatments. The longitudinal design of the proposed studies includes cardiovascular measures using echocardiography and telemetry, beginning at the first stress exposure and continuing until weaning. These measures will track the evolution of psychosocial stress- evoked cardiac stress across the postpartum period, providing translationally relevant information about effects of stress on cardiovascular function and morphology, and insights into therapeutically relevant interventions. Project Number: 1R01HL179186-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Fiona Hollis (+1 co-PI) | Institution: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA, COLUMBIA, SC | Award Amount: $727,080 | Activity Code: R01 | Study Section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17918601