妊娠中のカロリー制限は、神経発達障害への影響を伴う内皮の転写状態と血液脳関門の完全性を再プログラムする

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.