Prenatal Inflammation as a Determinant of Long-Term Cardiovascular Risk: Evidence from a Murine Model
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Background
Intrauterine inflammation is associated with increased lifetime cardiovascular disease (CVD) risk in offspring, yet long-term molecular mechanisms remain underexplored. We investigated the lasting cardiometabolic, hemodynamic, and vascular effects of prenatal inflammatory exposure in adult offspring using a mouse model.
Methods
On day 15 of gestation, pregnant CD-1 mice were randomized to receive intraperitoneal (IP) injections of either lipopolysaccharide (LPS group) or saline (SAL group). Blood samples were collected before and after injection to measure IL-6 concentrations. Blood pressure (BP) in offspring was measured at 6-8 months of age using the tail-cuff method, and tissues were collected. Protein was extracted from the brain cortex to measure cytokines utilizing the xMAP Luminex assay. The C-reactive protein (CRP) was measured in serum. Gene expression of IL-6, NOS3, NFkB, AT-1, and Trp53 was determined by RT-qPCR in the aorta. The experimental unit was a mother. Results were analyzed using the appropriate statistical methods.
Results
Maternal LPS administration induced significant acute systemic inflammation (P<0.05 for IL-6). At 6-8 months after delivery, maternal circulating CRP was significantly higher in LPS mice as compared to SAL (P=0.02). In offspring at 6-8 months of age, systolic BP was significantly elevated in LPS groups compared with SAL animals (P=0.04). LPS-exposed offspring exhibited higher total body and visceral adipose tissue weights. Aortic expression of the angiotensin II type 1 receptor (AT1) and NFkB were significantly upregulated (P=0.04 and P=0.03, respectively). Cortices of LPS offspring displayed a pro-inflammatory profile with increased total Inflammatory score, elevated pro-inflammatory IL-1β, and reduced anti-inflammatory IL-4 and IL-10. Furthermore, protective Trp53 gene expression was significantly downregulated in both the aorta (P=0.01) and heart (P=0.04).
Conclusions
A single mid-gestation inflammatory insult programs long-term cardio-inflammatory perturbations in offspring and results in long-term systemic inflammation in mothers. Prenatal LPS exposure induces persistent visceral obesity, hypertension, vascular RAS upregulation, central neuroinflammation, and cardiac/vascular Trp53 suppression in adult offspring, offering a mechanistic link between prenatal inflammation and offspring CVD risk.
