Vascular biology
Abstract
BACKGROUND Obesity, a growing health concern, often leads to metabolic disturbances, systemic inflammation, and vascular dysfunction. Emerging evidence suggests that adipose tissue-derived extracellular vesicles (adiposomes) may propagate obesity-related complications. However, their lipid composition and effect on cardiometabolic state remain unclear.METHODS This study examined the lipid composition of adiposomes in 122 participants (75 in obesity group, 47 in lean group) and its connection to cardiometabolic risk. Adiposomes were isolated via ultracentrifugation and characterized using nanoparticle tracking and comprehensive lipidomic analysis by mass spectrometry. Cardiometabolic assessments included anthropometry, body composition, glucose-insulin homeostasis, lipid profiles, inflammatory markers, and vascular function.RESULTS Compared with lean controls, individuals with obesity exhibited elevated adiposome release and shifts in lipid composition, including higher ceramides, free fatty acids, and acylcarnitines, along with reduced levels of phospholipids and sphingomyelins. These alterations strongly correlated with increased BMI, insulin resistance, systemic inflammation, and impaired vascular function. Pathway enrichment analyses highlight dysregulation in glycerophospholipid and sphingolipid metabolism, bile secretion, proinflammatory pathways, and vascular contractility. Machine-learning models utilizing adiposome lipid data accurately classified obesity and predicted cardiometabolic conditions, such as diabetes, hypertension, dyslipidemia, and liver steatosis, achieving accuracy above 85%.CONCLUSION Obesity profoundly remodels the adiposome lipid landscape, linking lipid changes to inflammation, metabolic dysfunction, and vascular impairment. These findings underscore adiposome lipids as biomarkers for obesity and related cardiometabolic disorders, supporting personalized interventions and offering therapeutic value in risk stratification and treatment.FUNDING This project was supported by NIH grants R01HL161386, R00HL140049, P30DK020595 (PI: AMM), R01DK104927, and P30DK020595 as well as by a VA Merit Award (1I01BX003382, PI: BTL).
Authors
Abeer M. Mahmoud, Imaduddin Mirza, Elsayed Metwally, Mohammed H. Morsy, Giorgia Scichilone, Monica C. Asada, Amro Mostafa, Francesco M. Bianco, Mohamed M. Ali, Mario A. Masrur, Chandra Hassan, Brian T. Layden
Abstract
Systemic arterial stenosis, including moyamoya disease (MMD) and middle aortic syndrome (MAS), is a rare condition of unclear etiology. MMD is a cerebral angiopathy, and MAS affects the abdominal and thoracic aorta. Although some genetic associations with MAS have been identified, the causes remain elusive. In this study, de novo heterozygous missense variants of RING finger protein 213 (RNF213) (p.His4058Pro and p.Thr4155Pro) in 2 unrelated families with MAS and MMD were studied by whole-exome sequencing. To elucidate the significance of these variants, we produced knockin mice carrying the Rnf213 p.His4058Pro variant. Homozygous knockin mice exhibited perinatal lethality because of respiratory failure and lung dysplasia, suggesting that this variant is pathogenic. Lung dysplasia in homozygous knockin mice was associated with upregulated innate immunity and inflammatory responses and downregulated cell proliferation. These findings suggested that in mice, the RNF213 p.His4058Pro variant plays critical roles in regulation of innate immunity and inflammation that affect lung development, revealing the complexity of RNF213 function in various tissues and species. In conclusion, this study provides insights into the genetic basis of MAS and MMD, highlights the potential involvement of RNF213 variants in systemic vasculopathy, and identifies unexpected associations with lung development and immune processes.
Authors
Ayako Kashimada, Tomoko Mizuno, Eriko Tanaka, Susumu Hosokawa, Tomohiro Udagawa, Yuichi Hiraoka, Keisuke Uchida, Tomohiro Morio, Kenjiro Kosaki, Masatoshi Takagi
Abstract
Vascular smooth muscle cells (VSMCs) exhibit significant heterogeneity and plasticity, enabling them to switch between contractile and synthetic states, which is crucial for vascular remodeling. NEXN has been identified as a high confidence gene associated with dilated cardiomyopathy (DCM). Existing evidence indicate NEXN is involved in phenotypic switching of VSMCs. However, a comprehensive understanding of the cell-specific roles and precise mechanisms of NEXN in vascular remodeling remains elusive. Using integrative transcriptomics analysis and smooth muscle specific lineage tracing mice, we demonstrate NEXN is highly expressed in VSMCs, and the expression of NEXN is significantly reduced during the phenotypic transformation of VSMCs and intimal hyperplasia induced by vascular injury. VSMC-specific NEXN deficiency promoted the phenotypic transition of VSMCs and exacerbated neointimal hyperplasia in mice following vascular injury. Mechanistically, we found NEXN primarily mediated VSMCs proliferation and phenotypic transition through endoplasmic reticulum (ER) stress and KLF4 signaling. Inhibiting ER stress ameliorated VSMCs phenotypic transition by reducing cell cycle activity and proliferation caused by NEXN deficiency. These findings indicate targeting NEXN could be explored as a promising therapeutic approach for proliferative arterial diseases.
Authors
Zexuan Lin, Chaojie Wang, Zhuohua Wen, Zhaohui Cai, Wenjie Guo, Xin Feng, Zengyan Huang, Rongjun Zou, Xiaoping Fan, Canzhao Liu, Hanyan Yang
Abstract
Microvascular rarefaction substantially contributes to renal dysfunction following ischemia-reperfusion injury (IRI). We characterized the microRNA signature of extracellular vesicles (EVs) released during endothelial apoptosis to identify biomarkers and regulators of microvascular rarefaction and renal dysfunction. Using in vitro models and RNA-Seq, we found miR-423-5p, let-7b-5p, and let-7c-5p enriched in small EVs from apoptotic endothelial cells. In mouse models of renal IRI and a cohort of 51 patients who have undergone renal transplant with delayed graft function, serum miR-423-5p correlated with circulating EVs, while let-7b-5p and let-7c-5p were also present in free form. Early acute kidney injury saw increased serum miR-423-5p levels linked to small EVs with endothelial markers. Over time, higher serum miR-423-5p levels were associated with large EVs and correlated with greater renal microvascular density and reduced fibrosis. Microvascular density and fibrosis predicted renal function 3 years after transplantation. We explored miR-423-5p’s role in renal homeostasis, finding that its injection during renal IRI preserved microvascular density and inhibited fibrosis. Endothelial cells transfected with miR-423-5p showed enhanced resistance to apoptosis, increased migration, and angiogenesis. Localized miR-423-5p injection in hindlimb ischemia model accelerated revascularization. These findings position miR-423-5p as a predictor of renal microvascular rarefaction and fibrosis, highlighting potential strategies for preserving renal function.
Authors
Francis Migneault, Hyunyun Kim, Alice Doreille, Shanshan Lan, Alexis Gendron, Marie-Hélène Normand, Annie Karakeussian Rimbaud, Martin Dupont, Isabelle Bourdeau, Éric Bonneil, Julie Turgeon, Sylvie Dussault, Pierre Thibault, Mélanie Dieudé, Éric Boilard, Alain Rivard, Héloïse Cardinal, Marie-Josée Hébert
Abstract
Single dose radiotherapy (SDRT) is a highly-curative modality that may transform radiotherapy practice. Unfortunately, only ~50% of oligometastatic lesions are SDRT treatable due to adjacent radiosensitive normal organs at risk. Here we address extent to which an anti-angiogenic drug, VEGFR2-antagonist DC101, radiosensitizes SDRT using murine MCA/129 fibrosarcomas and Lewis Lung Carcinomas, which display a dose range for SDRT lesional eradication virtually identical to that employed clinically (10-30Gy). SDRT induces unique tumor cure, stimulating rapid endothelial acid sphingomyelinase (ASMase)/ceramide signaling that yields marked vasoconstriction and perfusion defects in tumor xenografts and human oligometastases. Ensuing tumor parenchymal oxidative damage initiates a SUMO Stress Response (SSR), which inactivates multiple homologous recombination repair enzymes, radiosensitizing all tumor types. While VEGF inhibits neo-angiogenic ASMase, optimal radiosensitization occurs only upon anti-angiogenic drug delivery at ~1h preceding SDRT. Obeying these principles, we find DC101 radiosensitizes SSR, DNA double strand break unrepair and tumor cure by 4-8Gy at all clinically-relevant doses. Critically, DC101 fails to sensitize small intestinal endothelial injury or lethality from the gastrointestinal-acute radiation syndrome.
Authors
Jin Cheng, Liyang Zhao, Sahra Bodo, Prashanth K. B. Nagesh, Rajvir Singh, Adam O. Michel, Regina Feldman, Zhigang Zhang, Simon N. Powell, Zvi Fuks, Richard Kolesnick
Abstract
There is an emerging role for Stimulator of interferon genes (STING) signaling in pulmonary hypertension (PH) development. Related, prior resesarch has demonstrated the relevance of the immune checkpoint protein Programmed death ligand 1 (PD-L1) expression by immunoregulatory myeloid cells in PH. However, there remains a need to elucidate the cell-specific role of STING expression, and the STING/PD-L1 signaling axis in PH, before readily available disease-modifying therapies can be applied to patients with disease. Here, through generation of bone marrow chimeric mice, we show that STING-/- mice receiving wild-type (WT) bone marrow are protected against PH secondary to chronic hypoxia. We further demonstrate a cellular dichotomous role for STING in PH development with STING expression by smooth muscle cells contributing to PH, and its activation on myeloid cells being pivotal in severe disease prevention. Finally, we provide evidence that a STING-PD-L1 axis modulates disease severity, suggesting future potential therapeutic applications. Overall, these data provide concrete evidence of STING involvement in PH in a cell-specific manner, establishing biologic plausibility for cell-targeted STING-related therapies in PH treatment.
Authors
Ann T. Pham, Shiza Virk, Aline C. Oliveira, Matthew D. Alves, Chunhua Fu, Yutao Zhang, Jimena Alvarez-Castanon, Brian B. Lee, Keira L. Lee, Radwan Mashina, Katherine E. Ray, Patrick Donabedian, Elnaz Ebrahimi, Harsh Patel, Reeha Patel, Duncan Lewis, Zhiguang Huo, Harry Karmouty-Quintana, Li Chen, Lei Jin, Andrew J. Bryant
Abstract
Pathologic implications of dysregulated pulmonary vascular metabolism to pulmonary arterial hypertension (PAH) are increasingly recognized, but their clinical applications have been limited. We hypothesized that metabolite quantification across the pulmonary vascular bed in connective tissue disease–associated (CTD-associated) PAH would identify transpulmonary gradients of pathobiologically relevant metabolites, in an exercise stage–specific manner. Sixty-three CTD patients with established or suspected PAH underwent exercise right heart catheterization. Using mass spectrometry–based metabolomics, metabolites were quantified in plasma samples simultaneously collected from the pulmonary and radial arteries at baseline and during resistance-free wheeling, peak exercise, and recovery. We identified uptake and excretion of metabolites across the pulmonary vascular bed, unique and distinct from single vascular site analysis. We demonstrated the physiological relevance of metabolites previously shown to promote disease in animal models and end-stage human lung tissues, including acylcarnitines, glycolytic intermediates, and tryptophan catabolites. Notably, pulmonary vascular metabolite handling was exercise stage specific. Transpulmonary metabolite gradients correlated with hemodynamic endpoints largely during free-wheeling. Glycolytic intermediates demonstrated physiologic significance at peak exercise, including net uptake of lactate in those with more advanced disease. Contribution of pulmonary vascular metabolism to CTD-PAH pathogenesis and therapeutic candidacy of metabolism modulation must be considered in the context of physiologic stress.
Authors
Michael H. Lee, Thaís C. F. Menezes, Julie A. Reisz, Francesca I. Cendali, Eloara V. M. Ferreira, Jaquelina S. Ota-Arakaki, Priscila A. Sperandio, Rahul Kumar, Claudia Mickael, Martin M. Ieong, Juliana Lucena Santos, Ana Carolina B. Duarte, Dara C. Fonseca Balladares, Kevin Nolan, Rubin M. Tuder, Paul M. Hassoun, Angelo D’Alessandro, Rudolf K. F. Oliveira, Brian B. Graham
Abstract
Vascular smooth muscle cells (VSMCs) possess significant phenotypic plasticity, shifting between a contractile phenotype and a synthetic state for vascular repair/remodelling. Dysregulated VSMC transformation, marked by excessive proliferation and migration, primarily drives intimal hyperplasia. N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotes, plays a critical role in gene expression regulation; however, its impact on VSMC plasticity is not fully understood. This research investigates the alterations in m6A modification and its regulatory factors during VSMC phenotypic shifts and their influence on intimal hyperplasia. We demonstrate that METTL14, crucial for m6A deposition, significantly promotes VSMC dedifferentiation. METTL14 expression, initially negligible, is elevated in synthetic VSMC cultures, post-injury neointimal VSMCs, and human restenotic arteries. Reducing METTL14 in mouse primary VSMCs decreases pro-synthetic genes, suppressing their proliferation and migration. m6A-RIP-seq profiling shows key VSMC gene networks undergo altered m6A regulation in Mettl14-deficient cells. METTL14 enhances KLF4 and SERPINE1 expression through increased m6A deposition. Local METTL14 knockdown significantly curbs neointimal formation post-arterial injury, and reducing METTL14 in hyperplastic arteries halts further neointimal development. We found that METTL14 is a pivotal regulator of VSMC dedifferentiation, influencing KLF4- and SERPINE1-mediated phenotypic conversion. Inhibiting METTL14 is a viable strategy for preventing restenosis and halting restenotic occlusions.
Authors
Grace Chensee, Bob S.L. Lee, Immanuel D. Green, Jessica Tieng, Renhua Song, Natalia Pinello, Quintin Lee, Majid Mehravar, David A. Robinson, Mian Wang, Mary M. Kavurma, Jun Yu, Justin Jong Leong Wong, Renjing Liu
Abstract
Despite the accumulation of cisplatin in proximal tubules, direct visualization of the surrounding peritubular microcirculation, including its alteration in cisplatin-induced acute kidney injury (AKI), is lacking. Here, using fluorescence and cellular angiography through video-rate high-resolution intravital microscopy, progressive disturbance of peritubular microcirculation in cisplatin-induced AKI in mice was demonstrated. Fluorescence angiography revealed increasing perfusion defects, with a stepwise rise in time to peak (TTP), originating from capillaries surrounding S1 segments. Cellular angiography demonstrated a progressive decrease in the velocity and track length of individual erythrocytes during AKI progression, accompanied by a sequential decrease in the functional capillary ratio (FCR). Alterations in the perfusion area, TTP, and FCR preceded significant changes in blood urea nitrogen and cystatin C, suggesting the potential for early diagnosis. Although neutrophil infiltration near proximal tubules increased throughout the progression, it did not cause obstruction of the peritubular microcirculation. Depletion of neutrophils increased mortality due to systemic side effects, whereas functional inactivation of neutrophils using an anti-CD11b antibody improved peritubular microcirculation in cisplatin-induced AKI. This approach enables direct visualization and quantification of peritubular microcirculation and immune cell dynamics, providing insights into renal pathophysiology and potential therapeutic strategies.
Authors
Inwon Park, Seonghye Kim, Young Woo Um, Hee Eun Kim, Jae Hyuk Lee, Sejoong Kim, PILHAN KIM, You Hwan Jo
Abstract
The notion of clonal cell populations in human atherosclerosis has been suggested but not demonstrated. Somatic mutations are used to define cellular clones in tumors. Here, we characterized the mutational landscape of human carotid plaques through whole-exome sequencing to explore the presence of clonal cell populations. Somatic mutations were identified in 12 of 13 investigated plaques, while no mutations were detected in 11 non-atherosclerotic arteries. Mutated clones often constituted over 10% of the sample cell population, with genes related to the contractile apparatus enriched for mutations. In CHIP (clonal hematopoiesis of indeterminate potential) carriers, hematopoietic clones had infiltrated the plaque tissue and constituted substantial fractions of the plaque cell population alongside locally expanded clones. Our findings establish somatic mutations as a common feature of human atherosclerosis and demonstrate the existence of mutated clones expanding locally, as well as CHIP clones invading from the circulation. While our data do not support plaque monoclonality, we observe a pattern suggesting the coexistence of multiple mutated clones of considerable size spanning different regions of plaques. Mutated clones are likely to be relevant to disease development, and somatic mutations will serve as a convenient tool to uncover novel pathological processes of atherosclerosis in future studies.
Authors
Lasse Bach Steffensen, Stephanie Kavan, Pia Søndergaard Jensen, Matilde Kvist Pedersen, Steffen Møller Bøttger, Martin J. Larsen, Maja Dembic, Otto Bergman, Ljubica Matic, Ulf Hedin, Lars vB Andersen, Jes Sanddal Lindholt, Kim Christian Houlind, Lars P. Riber, Mads Thomassen, Lars Melholt Rasmussen
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