Mutations in the AARS2 gene are linked to infantile cardiomyopathy; however, the underlying molecular mechanism remains unknown. Here, we report that PCBP1, a poly(rC) binding protein, interacts with the AARS2 transcript to mediate its alternative splicing. Cardiomyocyte-specific deletion of Pcbp1 in mice impairs normal splicing and causes premature termination of Aars2, leading to defects in heart development and postnatal lethality. Similarly, mice with a deletion in Aars2 that mimics a disease-causing splicing lesion display heart developmental abnormalities, reminiscent of those in patients with infantile mitochondrial cardiomyopathy. Mechanistically, loss of Pcbp1 or Aars2 in the heart reduces oxidative phosphorylation, a hallmark of patients with AARS2 mutations. This reduction in mitochondrial-encoded proteome activates mitonuclear communication and the UPR pathway, thereby inducing a compensatory nuclear-encoded mitochondrial gene program. Our findings provide insights into the PCBP1-AARS2 regulatory axis in mitochondrial cardiomyopathy.

Endocytic adaptor proteins are essential regulators of intracellular trafficking, coupling receptor internalization with downstream signaling. Recent discoveries have deepened our understanding of how endocytic adaptor proteins contribute to both physiological and pathological processes in the vascular system. This review summarizes the emerging roles of key adaptor proteins—such as epsins, disabled-2, and adaptor protein 2—across multiple vascular cell types, including endothelial cells, vascular smooth muscle cells, and macrophages. These adaptors have diverse but essential functions, ranging from regulating angiogenic signaling and maintaining endothelial barrier integrity to modulating inflammatory responses, vascular smooth muscle cells phenotypic switching, lipid uptake, and structural remodeling of blood vessels. We also highlight advances in therapeutic strategies, such as nanomedicine, viral expression vectors, DNA nanostructures, and small molecule inhibitors that target endocytic adaptors and their function. Understanding the diverse and cell-specific roles of endocytic adaptor proteins is important for gaining insights into vascular disease mechanisms and uncovering novel targets for therapeutic interventions. 

Microplastics (MPs) are small plastic particles emerging as significant environmental pollutants and humans are ubiquitously exposed to MPs. MPs can be detected in human atherosclerotic plaques and are associated with a higher risk of cardiovascular disease (CVD) and stroke in humans. However, the impact of MP exposure on the cardiovascular system remains elusive. In the current study, we investigated the effects of exposure to MPs at an environmentally relevant dose on atherosclerosis development in male and female low-density lipoprotein receptor-deficient (LDLR^-/-) mice. LDLR^-/- mice were fed a semisynthetic low-fat (4.3 %), low-cholesterol (0.02 %) diet and exposed to 10 mg/kg body weight MPs via daily oral gavage for 9 weeks. Male and female LDLR^-/- mice fed the low-fat diet did not develop obesity phenotype and exposure to MPs did not affect adiposity and circulating lipid profiles in those lean mice. Intriguingly, MP exposure increased atherosclerotic lesion areas in the aortic root by 63 % (p = 0.0185) and brachiocephalic artery by 624 % (p = 0.0541) in male LDLR^-/- mice but did not significantly affect atherosclerosis in female mice. Single-cell RNA sequencing analysis of the whole aorta revealed that exposure to MPs affected the proportions and cellular processes of key atherogenesis-related cell types, especially endothelia cells. Consistently, MP exposure induced pro-atherogenic gene expression in murine primary endothelia cells and human endothelial cells in vitro. Our findings reveal the sex-specific atherogenic effects of MPs in vivo and provide mechanistic insights and new understanding of the impact of MPs on atherosclerosis development and CVD risk in humans.

Background: Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-laden foam cells and plaques within the arterial wall. Dysfunctional vascular smooth muscle cells (VSMCs), fibroblasts, endothelial cells (ECs), and macrophages contribute to disease progression. Here, we report that macrophage-specific expression of epsins, highly conserved endocytic adaptor proteins involved in clathrin-mediated endocytosis, accelerates atherosclerosis in Western diet (WD)-fed mice.

Methods: Apoe-deficient (WT/Apoe^-/-) mice and littermates with a myeloid-specific deletion of epsin 1/2 on an Apoe^-/- background (LysM-DKO/Apoe^-/-) were generated and fed a WD for 16 weeks. Single-cell RNA sequencing (scRNA-seq) was conducted to investigate the cellular and molecular mechanisms regulated by macrophage epsins during atherosclerosis. Findings from scRNA-seq were validated through metabolic profiling, qRT-PCR, immunostaining, and co-culture experiments to assess associated phenotypic changes.

Results: LysM-DKO/Apoe^-/- mice exhibited significantly reduced atherosclerotic foam cell formation compared to WT/Apoe^-/- controls. scRNA-seq analysis identified 19 major cell types, including six VSMC and five macrophage subpopulations. Modulated VSMC1 and VSMC2 subtypes were associated with inflammation, migration, and VSMC-to-macrophage transition. These populations, along with foamy-Trem2 and inflammatory macrophages, were markedly reduced in LysM-DKO/Apoe^-/- mice. Transition of modulated VSMC2 subtype into macrophages was significantly inhibited, as confirmed by both computational analysis and experimental validation. Additionally, macrophage epsin deletion reversed endothelial dysfunction, suppressed cholesterol- and glucose-mediated signaling, and reduced expression of pro-inflammatory ligands IL-1β and TNF-⍺.

Conclusion: Macrophage epsin deletion limits foam cell formation and preserves VSMC and endothelial cell phenotypes and functions. These findings reveal a potential therapeutic strategy targeting macrophage epsins to combat atherosclerosis.

Despite the development of potent drugs for modifiable risk factors, such as statins, and advances in mechanistic biomedical research, vascular disease remains the No.1 killer globally and represents a huge cost to public health. The underlying mechanisms remain incompletely understood and effective new therapies are needed. Such major challenges have promoted technological innovations and their implementations in vascular research. Unmet clinical needs and exponential technological development have synergistically advanced vascular medicine. Addressing the challenges associated with the complexity in treating cardiovascular disease requires integration of cross-disciplinary approaches and knowledge. This Research Topic thus reports new trends in a wide range of vascular medicine research from fundamental basic science to translational medicine to clinical studies.

Deciphering cell identity genes is pivotal to understanding cell differentiation, development, and cell identity dysregulation involving diseases. Here, we introduce SCIG, a machine-learning method to uncover cell identity genes in single cells. In alignment with recent reports that cell identity genes (CIGs) are regulated with unique epigenetic signatures, we found CIGs exhibit distinctive genetic sequence signatures, e.g. unique enrichment patterns of cis-regulatory elements. Using these genetic sequence signatures, along with gene expression information from single-cell RNA-seq data, SCIG uncovers the identity genes of a cell without a need for comparison to other cells. CIG score defined by SCIG surpassed expression value in network analysis to reveal the master transcription factors (TFs) regulating cell identity. Applying SCIG to the human endothelial cell atlas revealed that the tissue microenvironment is a critical supplement to master TFs for cell identity refinement. SCIG is publicly available at https://doi.org/10.5281/zenodo.14726426  , offering a valuable tool for advancing cell differentiation, development, and regenerative medicine research.

The lymphatic system maintains tissue fluid balance, and its dysfunction can result in lymphedema. Although cholesterol is essential for cellular function, its role in lymphatic development has remained unknown. Here, we identify APOA1 binding protein (AIBP) as a key regulator that promotes lymphatic endothelial cell fate specification and lymphangiogenesis. Mechanistically, AIBP reduces plasma membrane cholesterol content, thereby enhancing VEGFR3 signaling by disrupting caveolae—small plasma membrane invaginations formed by the scaffolding protein caveolin-1 (CAV-1)—and relieving CAV-1–mediated inhibition. In zebrafish and mice, AIBP loss impairs VEGFR3 signaling and lymphatic development, defects that can be rescued by CAV-1 deletion or by a VEGFR3 mutant (VEGFR3^AAA) lacking CAV-1 binding. Administration of recombinant AIBP augments VEGFC-induced lymphangiogenesis and accelerates the resolution of secondary lymphedema in adult mice. These findings define the AIBP–CAV-1 axis as a regulator of VEGFR3 signaling and lymphatic growth, offering potential therapeutic opportunities for treating lymphatic dysfunction.

Efficient lymph flow is ensured by lymphatic valves (LVs). The mechanisms that regulate LV development are incompletely understood. Here, we show that the deletion of the GPCR sphingosine 1-phosphate receptor-1 (S1PR1) from lymphatic endothelial cells (LECs) results in fewer LVs. Interestingly, LVs that remained in the terminal ileum-draining lymphatic vessels were specifically dysfunctional. Furthermore, tertiary lymphoid organs (TLOs) formed in the terminal ileum of the mutant mice. TLOs in this location are associated with ileitis in humans and mice. However, mice lacking S1PR1 did not develop obvious characteristics of ileitis. Mechanistically, S1PR1 regulates shear stress signaling and the expression of the valve-regulatory molecules FOXC2 and connexin-37. Importantly, Foxc2^+/− mice, a model for lymphedema-distichiasis syndrome, also develop TLOs in the terminal ileum. Thus, we have discovered S1PR1 as a previously unknown regulator of LV and TLO development. We also suggest that TLOs are a sign of subclinical inflammation that can form due to lymphatic disorders in the absence of ileitis.

Diabetes mellitus can cause impaired and delayed wound healing, leading to lower extremity amputations; however, the mechanisms underlying the regulation of vascular endothelial growth factor (VEGF)-dependent angiogenesis remain unclear. In our study, the molecular underpinnings of endothelial dysfunction in diabetes are investigated, focusing on the roles of Disabled-2 (Dab2) and Forkhead Box M1 (FOXM1) in VEGF receptor 2 (VEGFR2) signaling and endothelial cell function. Bulk RNA-sequencing analysis identified significant downregulation of Dab2 in high glucose treated primary mouse skin endothelial cells. In diabetic mice with endothelial deficiency of Dab2, in vivo and in vitro angiogenesis and wound healing were reduced when compared with wild-type diabetic mice. Restoration of Dab2 expression by injected mRNA-containing LyP-1-conjugated lipid nanoparticles (LNPs) rescued impaired angiogenesis and wound healing in diabetic mice. Furthermore, FOXM1 was downregulated in skin endothelial cells under high glucose conditions as determined by RNA-sequencing analysis. FOXM1 was found to bind to the Dab2 promoter, regulating its expression and influencing VEGFR2 signaling. The FOXM1 inhibitor FDI-6 reduced Dab2 expression and phosphorylation of VEGFR2. Our study provides evidence of the crucial roles of Dab2 and FOXM1 in diabetic endothelial dysfunction and establishes targeted delivery as a promising treatment for diabetic vascular complications.