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Prenatal caloric restriction reprograms endothelial transcriptional states and blood-brain barrier integrity:
J M Zúñiga-Hernández1, I Peña-Villalobos2, H J Garay1
1Laboratory of Stem Cells and Developmental Biology, Department of Biology, Faculty of Sciences, Universidad de Chile, Chile.
Insights
Prenatal caloric restriction (RP) reprograms brain endothelial cells, altering their response to adult nutritional stress. This "two-hit" model suggests early-life diet compromises neurovascular integrity, potentially impacting brain health.
Area of Science:
- Neuroscience
- Developmental Biology
- Vascular Biology
Background:
- Prenatal caloric restriction (RP) causes lasting metabolic and neurobehavioral changes.
- The impact of RP on cerebrovascular programming and adult nutritional stress responses is unclear.
- RP offspring show hypoactivity and anxiety, suggesting neurobehavioral alterations.
Purpose of the Study:
- Investigate how RP acts as a "first hit" to program brain endothelial cells.
- Determine how adult caloric restriction (CR) as a "second hit" modifies these programs.
- Profile endothelial transcriptional states under different nutritional conditions.
Main Methods:
- Utilized RNA sequencing and cell-type deconvolution.
- Examined four nutritional conditions: ad libitum controls (AL-AL), adult restriction only (AL-CR), prenatal restriction only (RP-AL), and combined restriction (RP-CR).
- Analyzed endothelial transcriptional states in mice.
Main Results:
- RP induced significant transcriptional changes in endothelial cells, including enrichment of angiogenic tip-cell signatures.
- Prenatal imprints altered the endothelial response to adult CR, indicating modified adaptive plasticity.
- Genes Kdr, Hdac7, and Mmrn2 were significantly regulated and correlated with angiogenic pathways, especially in the "two-hit" paradigm.
Conclusions:
- Early-life nutritional programming establishes endothelial transcriptional states that influence later-life responses.
- A "two-hit" model suggests prenatal restriction compromises neurovascular integrity, creating vulnerability.
- This vascular vulnerability may contribute to psychiatric disorders like schizophrenia.
Abstract:
Prenatal caloric restriction (RP) induces long-lasting physiological adaptations that shape adult metabolism and brain function, yet its impact on cerebrovascular programming and responses to later-life nutritional stress remains poorly understood. We previously showed that RP offspring exhibit hypoactivity and anxiety-like behaviors in adulthood, suggesting persistent neurobehavioral alterations. Here, we investigated how RP acts as a developmental "first hit" to program brain endothelial transcriptional states, and how a subsequent adult caloric restriction (CR) functions as a "second hit" that adjust these pre-established programs in mice. Using RNA sequencing combined with cell-type deconvolution, we profiled endothelial transcriptional states across four nutritional conditions: ad libitum controls (AL-AL), adult restriction only (AL-CR), prenatal restriction only (RP-AL), and combined restriction (RP-CR). RP induced robust transcriptional changes, consistent with endothelial reprogramming characterized by enrichment of angiogenic tip-cell signatures and modulation of genes involved in blood-brain barrier integrity and vascular stability. Importantly, these prenatal imprints conditioned the endothelial transcriptional response to adult CR, revealing altered adaptive plasticity rather than a naïve angiogenic response. Notably, three genes-Kdr, Hdac7, and Mmrn2-were significantly regulated and strongly correlated with GSVA scores of angiogenic pathways, particularly under the two-hit dietary paradigm. Collectively, these genes integrate pro-angiogenic signaling (Kdr), epigenetic control of endothelial identity (Hdac7), and extracellular matrix-mediated vascular stabilization (Mmrn2), collectively defining endothelial states shaped by recurrent nutritional stress. Our findings support a two-hit model in which early-life transcriptional reprogramming compromises neurovascular integrity, potentially establishing a vascular vulnerability that contributes to the etiology of psychiatric disorders such as schizophrenia.
