Cheng-Chao Ruan

Vascular smooth muscle cell (VSMC) heterogeneity drives region-specific aortic pathologies, yet the roles of somite-derived lineages remain unclear. Utilizing Myf5 and MyoD lineage tracing alongside a smooth muscle-specific Myf5 conditional knockout model, we show that Myf5-derived cells selectively populate the thoracic aortic media, whereas the MyoD lineage completely spares large arteries. Early embryonic Myf5 deletion suppressed embryonic VSMC proliferation and downregulated α-SMA, reduced the synthesis of elastic, establishing its necessity in aortic morphogenesis. Upon in vitro ox-LDL challenge and calcification induction, the non-Myf5 lineage primarily drives excessive proliferation and osteogenic transdifferentiation, whereas Myf5 lineage VSMCs exhibit remarkable phenotypic stability and resistance to PDGF-BB-induced dedifferentiation compared to their non-Myf5 counterparts. Collectively, our findings demonstrate a strict lineage divergence between Myf5 and MyoD, suggesting that Myf5 lineage cells play an important role in maintaining aortic integrity, and uncover a lineage-imprinted plasticity that explains regional vascular heterogeneity.

Interactions between nervous system and adipose tissue are involved in the regulation of adipocyte browning. However, whether microglial activation participates in the regulation of cold exposure-induced sympathetic innervation and adipocyte browning is unclear. Here, we demonstrate that RNA m6A demethylase ALKBH5 in the microglia nucleus of hypothalamus (PVH) region inhibits cold exposure-induced adipocyte browning in the subcutaneous white adipose tissue (sWAT) of male mice. The single nuclear-RNA sequencing, brain slice electrophysiological assay and pathological analyses show that microglia-specific ALKBH5 knockout (MCKO) enhances sympathetic activation and adipocyte browning in the sWAT during cold exposure. Mechanistically, MCKO enhances m6A methylation of Ntf5 mRNA and upregulates Ntf5 expression in the microglia. Ntf5 then activates PVH-TrkB neurons and downstream sympathetic innervation in the sWAT. During aging, MCKO prevents brown adipocyte decline in the sWAT, and promotes metabolic activity. These findings fill a gap in the research of microglia in neuron-mediated adipocyte browning, and suggest that microglia may be a potential therapeutic target for the treatment of individuals with metabolic disorders.

Adipose tissue is a complex endocrine organ that critically regulates cardiovascular health and disease. Different adipose depots vary in location and function, exerting distinct physiological and pathological effects on the cardiovascular system. This review examines the roles of three key depots: (1) epicardial adipose tissue (EpAT), (2) perivascular adipose tissue (PVAT), and (3) bone marrow adipose tissue (BMAT). We also focus on the functional differentiation of adipose tissue based on its anatomical location to provide a robust understanding of its diverse impacts on cardiovascular diseases (CVDs). We further explore pharmacological interventions targeting adiposity and obesity, including their mechanisms, clinical applications, and therapeutic potential in CVD management. By elucidating the intricate interactions between adipose depot dynamics and cardiovascular pathology, this work highlights emerging research directions and underscores the need for adipose-specific strategies in cardiovascular therapeutics.

Transdifferentiation of one cell type into another occurs under normal physiological conditions. Adipose tissue is an important metabolic and endocrine organ involved in the onset and progression of various diseases. Previous studies have shown that fibroblasts can transdifferentiate into adipocytes. Here, we demonstrate that CX3CR1-derived cells can also transdifferentiate into adipocytes. Additionally, RFP⁺ SVF cells and mature adipocytes were identified in different adipose tissues of Cx3cr1^cre: Rosa26^Td mice. Cold exposure enhances the adipogenic transdifferentiation of RFP⁺ cells, whereas a high-fat diet (HFD) inhibits this process. Mechanistically, we found that PPARγ regulates transdifferentiation, suggesting its role in the differentiation of CX3CR1-derived cells into adipocytes, thus offering new insights into the origin of adipocytes in the body.

Vascular tissue-resident macrophages (VRMs) maintain immune balance in blood vessels, but their role in abdominal aortic aneurysm (AAA) development remains unclear. Here we demonstrated that a specific group of VRMs located in the adventitia marked by expression of Lyve1, protected against AAA by secreting the extracellular matrix protein Sparcl1 (Sc1). Deletion of Sc1 in VRMs promoted dysfunctional lymphangiogenesis and led to the formation of tertiary lymphoid structures (TLSs), thereby accelerating AAA progression. Mechanistically, the calcium-binding domain of Sc1 acted as a trap for the growth factor FGF2, inhibiting FGF2-mediated dysfunctional lymphangiogenesis and expression of genes associated with TLS formation. A therapeutic peptide derived from Sc1 (Spa17) mitigated AAA progression in several AAA models. Our findings reveal that VRM-derived Sc1 has a protective role in AAA and identify a potential therapeutic approach.

This study aimed to explore the potential correlation between the metabolic intermediate L-2-hydroxyglutarate (L-2-HG) and T cell exhaustion, as well as the underlying mechanisms involved. In this study, we investigated the presence of exhausted T (Tex) cells in patients under certain conditions: HIV infection, chronic leukemia, and hepatocellular carcinoma. To gain insights into the epigenetic signatures and transcriptome changes in Tex cells, we employed a combination of RNA-seq and ATAC-seq analyses. To evaluate the impact of L-2-HG on mitochondrial function, differentiation, and antitumor capacity of Tex cells, we utilized in vitro cell culture experiments and animal tumor models. We observed mitochondrial depolarization and metabolic dysfunction in Tex cells, accompanied by a significant reduction in L-2-HG levels. Moreover, altered epigenetic characteristics were observed in Tex cells, including a substantial increase in H3K27me3 abundance. Culturing Tex cells with L-2-HG demonstrated improved mitochondrial metabolism, reduced H3K27me3 abundance, and enhanced memory T cell differentiation. In a mouse melanoma tumor model, L-2-HG–treated CD8 ⁺ T cells for adoptive therapy led to significantly reduced tumor volume and significantly enhanced effector function of T cells. The study revealed that L-2-HG acted as an immune metabolite through epigenetic modifications of Tex cells.

Background and Aims: Members of the CCN matricellular protein family are crucial in various biological processes. This study aimed to characterize vascular cell-specific effects of CCN5 on neointimal formation and its role in preventing in-stent restenosis (ISR) after percutaneous coronary intervention (PCI). Methods: Stent-implanted porcine coronary artery RNA-seq and mouse injury-induced femoral artery neointima single-cell RNA sequencing were performed. Plasma CCN5 levels were measured by enzyme-linked immunosorbent assay. Endothelial cell (EC)- and vascular smooth muscle cell (VSMC)-specific CCN5 loss-of-function and gain-of-function mice were generated. Mass spectrometry and co-immunoprecipitation were conducted to identify CCN5 interacting proteins. Additionally, CCN5 recombinant protein (CCN5rp)-coated stents were deployed to evaluate its anti-ISR effects in a porcine model. Results: Plasma CCN5 levels were significantly reduced and correlated closely with the degree of restenosis in ISR patients. CCN5 expression was significantly decreased in VSMCs of stent-implanted porcine coronary segments and injured mouse femoral arteries, especially in synthetic VSMCs. In contrast, elevated CCN5 expression was observed in regenerating ECs of injured vessels. Endothelial cell- and VSMC-specific CCN5 deletion mice exhibited exacerbation of injury-induced neointimal hyperplasia, while CCN5 gain-of-function alleviated neointimal formation. Mechanistic studies identified thymosin β4 (Tβ4) as a CCN5 interacting protein in ECs and EC-CCN5 promoted injury repair through Tβ4 cleavage product Ac-SDKP. Also, CCN5rp promoted EC repair to suppress neointimal hyperplasia via interaction with Cd9 extracellular domain. Moreover, implantation with CCN5rp-coated stent significantly increased stent strut coverage with ECs, which suppressed neointimal formation and ultimately alleviated ISR. Conclusions: CCN5 exerts a dual protective effect on ISR by inhibiting VSMC proliferation and facilitating EC repair. CCN5rp-coated stent might be promising in the prevention of ISR after PCI.

EphrinB2 (erythropoietin-producing hepatoma interactor B2) is a key Eph/ephrin family member, promoting angiogenesis, vasculogenesis, and lymphangiogenesis during embryonic development. However, the role of EphrinB2 in cardiac lymphangiogenesis following myocardial infarction (MI) and the potential molecular mechanism remains to be demonstrated. This study revealed that EphrinB2 prevented ischemic heart post-MI from remodeling and dysfunction by activating the cardiac lymphangiogenesis signaling pathway. Deletion of EphrinB2 impaired cardiac lymphangiogenesis and aggravated adverse cardiac remodeling and ventricular dysfunction post-MI. At the same time, overexpression of EphrinB2 stimulated cardiac lymphangiogenesis which facilitated cardiac infiltrating macrophage drainage and reduced inflammation in the ischemic heart. The beneficial effects of EphrinB2 on improving clearance of inflammatory response and cardiac function were abolished in Lyve1 knockout mice. Mechanistically, EphrinB2 accelerated cell cycling and lymphatic endothelial cell proliferation and migration by activating CDK5 and CDK5-dependent ISL1 nuclear translocation. EphrinB2 enhanced the transcriptional activity of ISL1 at the VEGFR3 (FLT4) promoter, and VEGFR3 inhibitor MAZ51 significantly diminished the EphrinB2-mediated lymphangiogenesis and deteriorated the ischemic cardiac function. We uncovered a novel mechanism of EphrinB2-driven cardiac lymphangiogenesis in improving myocardial remodeling and function after MI.