Metabolic and Cardiovascular axis

Metabolic and hepatic outcomes related to intrauterine growth restriction

Individuals born after IUGR are at increased risk of developing metabolic syndrome (MetS) and nonalcoholic fatty liver disease in adulthood. Thanks to a rat model of IUGR rat induced by altered maternal nutrition during all gestation (9% casein vs. 23 % casein for control (CTRL) group), we investigated metabolic, hepatic, and visceral adipose tissue (VAT) alterations in six-month-old offspring. , comped to CTRL group, male IUGR rats—unlike females—displayed hallmark MetS features, including increased visceral fat mass, glucose intolerance and hepatic dysfunction characterized by elevated transaminases, lipid accumulation, and impaired lipogenic signaling. In VAT, male IUGR offspring exhibited pronounced adipocyte hypertrophy and hyperplasia, increased expression of adipogenic markers (PPAR γ, ZFP423), higher inflammatory cytokine levels (IL6, TNFalpha), and enhanced macrophage infiltration (CD68, ITGAM, ITGAX). Both VAT and liver showed evidence of oxidative stress (higher superoxide level and reduced antioxidant defenses) as well as markers of stress induced-premature senescence (SIPS) including lipofuscin accumulation, increased p16INK4a and altered Sirtuin-1 expression. No abnormalities appeared in females, while males showed linked adipose–hepatic dysfunction driving MetS risk after IUGR.

Dysfunction of endothelial colony-forming cells (ECFCs) related to intrauterine growth restriction

In the IUGR rat model previously described, we observed that in six-month-old offspring, only IUGR males have increased systolic blood pressure and microvascular rarefaction (tibial muscle). ECFCs isolated from bone marrow of IUGR vs. CTRL males displayed a decreased number, reduced proliferation, and an impaired capacity to form capillary-like structures, associated with altered angiogenic profile. These dysfunctions were associated with oxidative stress (higher superoxide anion levels, decreased superoxide dismutase protein expression, increased DNA damage) and SIPS (increased beta-galactosidase activity, increased p16^INK4a, decreased sirtuin-1 protein expression). IUGR females of the same age and from the same litter did not show ECFC alterations.  Adult IUGR male rats exhibit impaired ECFC functions associated with the onset of arterial hypertension. In contrast, the absence of such alterations in females may contribute to their preserved vascular health.

In vivo assessment of cardiac alterations using PET in a rat model of intrauterine growth restriction (IUGR)

IUGR affects 8–10% of pregnancies and is the second leading cause of perinatal mortality after prematurity. Adults born after IUGR show a higher risk of cardiovascular diseases, including hypertension, early cardiac remodeling, and ischemic and coronary heart disease, though underlying mechanisms remain unclear. In our established rat model, adult males (6 months) exhibit marked LV alterations compared with controls: reduced LV/tibia length ratio, fewer but larger cardiomyocytes, increased ANP mRNA expression, and signs of impaired angiogenesis (microvascular rarefaction, reduced VEGF‑A). These abnormalities are associated with oxidative stress and SIPS. Females show no detectable differences from controls. Building on these vitro findings, we aim to characterize in vivo myocardial function using PET imaging, the reference technique for non‑invasive evaluation of cardiac physiology. PET enables high‑resolution, quantitative monitoring of perfusion and molecular processes. We plan to assess:

• Myocardial perfusion, at rest and under adenosine stress, using ⁸²Rb‑PET
• Angiogenesis, using ⁶⁸Ga‑RGD‑PET

This approach will help elucidate sex‑specific mechanisms linking IUGR to adult cardiovascular dysfunction.