HDACs x VEGFR2

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.

Retinal neovascularization (RNV) is a serious pathological process that destroys the normal structure of the retina and leads to vision loss. Succinate, an important product of the tricarboxylic acid (TCA) cycle, has recently been discovered to play essential functions in inflammation and cardiovascular disease. In this research, we discovered that succinate can regulate macrophage phenotyping via the G protein‐coupled receptor 91 (GPR91) on the surface of macrophages. The induction of succinate polarized macrophages toward the M2 phenotype. Furthermore, studies revealed that succinate influences macrophage phenotypic direction by modulating the SIRT1/AMPKα pathway. Ex527 inhibited macrophage M2‐type polarization after succinate induction, preventing abnormal retinal vascular development in oxygen‐induced retinopathy (OIR) mice. Interestingly, we noticed an increase in RBP4 in macrophage supernatant after succinate induction. Exogenous RBP4 elevated VEGFR2 expression and tube formation in vascular endothelial cells. Meanwhile, the increase in VEGFR2 is possibly attributed to endocytosis. In summary, succinate regulates macrophage M2 polarization via the SIRT1/AMPKα pathway and mediates RNV formation. It also influences endothelial cell angiogenic capacity by promoting VEGFR2 internalization.

The development of dual-targeted inhibitors represents a promising strategy to address the challenges of drug resistance and limited efficacy in cancer therapy. This study describes the design, synthesis, and evaluation of novel inhibitors targeting VEGFR2 and HDAC through a structure-based pharmacophore-merging strategy. We integrated the hydroxamic acid zinc-binding group and the linker into the back pocket of VEGFR2. Molecular dynamics (MD) simulations and free energy perturbation (FEP) calculations facilitated the optimization of the inhibitors, ultimately leading to the discovery of compound 10i, which demonstrated significant dual-inhibitory activity. In vitro assays demonstrated its potent antiproliferative effects against cancer cell lines, particularly HT-29, while maintaining a favorable safety profile for normal cells. In vivo evaluation using HT-29 and HCCLM3/Sorafenib xenograft models confirmed robust tumor growth inhibition (TGI = 64.40% and 89.72%), with no significant toxicity observed. These findings underscore the therapeutic potential of compound 10i as a VEGFR2/HDAC dual inhibitor.