Vascular biology
Abstract
Abdominal aortic aneurysm (AAA) lacks effective pharmacological therapies. Here, we investigate transcription factor 7-like 2 (TCF7L2), a genetic locus associated with both thoracic and abdominal aortic aneurysms, to elucidate its role in AAA pathogenesis. Integrating summary-data-based Mendelian randomization (SMR) with single-cell RNA sequencing (scRNA-seq) of human and mouse aortas, we identify TCF7L2 as a gene enriched in vascular smooth muscle cells (VSMCs) and causally linked to AAA development. Smooth muscle cell-specific TCF7L2 knockout significantly attenuates AAA formation across three distinct murine models (Ang II infusion-, BAPN/Ang II co-administration-, and elastase-induced AAA), independent of systemic blood pressure or lipid levels. Mechanistic studies reveal that TCF7L2 directly upregulates MMP14 and downregulates TIMP3 expression in vitro and in vivo, driving MMP2-mediated extracellular matrix (ECM) degradation. Concurrently, TCF7L2 represses integrin β1 (ITGB1) expression, reducing VSMC adhesion to the ECM. Collectively, these findings identify TCF7L2 as a key driver of pathological vascular remodeling in AAA, suggesting that targeting TCF7L2 may offer a novel therapeutic strategy for limiting AAA progression.
Authors
Yongjie Deng, Yaozhong Liu, Yang Zhao, Hongyu Liu, Guizhen Zhao, Zhenguo Wang, Xu Zhang, Chao Xue, Wei Huang, Tianqing Zhu, Haocheng Lu, Yanhong Guo, Lin Chang, Ida Surakka, Y. Eugene Chen, Jifeng Zhang
Abstract
Aortic dissection or rupture is a leading cause of mortality in vascular Ehlers-Danlos syndrome (VEDS), a disorder caused by mutations in the COL3A1 gene. Col3a1G938D/+ mice recapitulate features of VEDS, including high risk of aortic rupture. As in people with VEDS, aortic risk in this model accelerates at the onset of puberty, especially in males. We identify developmentally regulated gene programs associated with this vulnerability and that are targeted by treatments that mitigate aortic risk. Both genetic and pharmacological inhibition of the androgen receptor (AR) eliminated survival differences between sexes, while treatment with a dual AR and mineralocorticoid receptor (MR) antagonist provided near-complete and durable protection in both sexes. Pathways targeted by dual AR/MR inhibition, including those related to extracellular matrix (ECM) organization and cell-ECM interactions, largely overlapped with those also modulated by isolated MR antagonism. Selective targeting of MR signaling emerged as an effective therapeutic strategy in both sexes that avoids sexual side effects in males.
Authors
Emily E. Juzwiak, Caitlin J. Bowen, Rhiannon Edwards, Leda Restrepo, Serena Lee, Cassie A. Parks, Anthony Zeng, Maya M. Black, Oscar E. Reyes Gaido, Emily E. Bramel, Dustin T. Shigaki, Michael A. Beer, Chiara Bellini, Harry C. Dietz, Elena Gallo MacFarlane
Abstract
Pulmonary fibrosis is frequently accompanied by pulmonary hypertension, which can occur disproportionate to the extent of fibrosis, suggesting a fibrosis-independent vascular remodeling process. Here, we demonstrated that plasma growth differentiation factor 15 (GDF15) is elevated across diverse fibrotic lung disease subtypes and correlates with markers of elevated right heart pressures, but not pulmonary function indices, indicating a possible link to endothelial cell dysfunction. To investigate the import of endothelial GDF15 as a modifier of lung fibrosis pathogenesis, we generated endothelial cell-specific Gdf15 knockout mice, which showed protection from bleomycin-induced lung injury and fibrosis, with preserved lung function. RNA sequencing of human pulmonary microvascular endothelial cells revealed altered expression of barrier-regulatory genes in GDF15-deficient endothelial cells compared to controls. Functional studies confirmed that GDF15 knockdown attenuates thrombin-induced barrier disruption by reducing cytosolic Ca2+ responses. Together, these findings implicate endothelial GDF15 as a modifier of vascular permeability and Ca2+ signaling, and a contributor to lung injury and fibrosis.
Authors
Kristen Raffensperger, Marta Bueno, Brian J. Philips, Megan Miller, Máté Katona, Shuai Yuan, Adriana Estrada-Bernal, Byron Chuan, Pavan Suresh, Stephanie Taiclet, Scott Hahn, Yingze Zhang, Jonathan K. Alder, Seyed Mehdi Nouraie, Daniel J. Kass, Oliver Eickelberg, Adam C. Straub
Abstract
Aortic dissection (AD) is a catastrophic vascular emergency with high mortality, and current pharmacologic interventions to prevent its progression are limited. Vascular smooth muscle cells (VSMCs) undergo a pathological phenotypic switch from a contractile to a synthetic state during AD, compromising aortic wall integrity; however, the underlying metabolic mechanisms remain poorly understood. In this study, we performed integrative transcriptomic analyses and identified glutaminase 1 (GLS1) as a key regulator of VSMC phenotypic switching in AD. GLS1 expression was significantly downregulated in VSMCs from both human AD aortic tissues and mouse models. Functionally, GLS1 deficiency promoted PDGF-BB–induced VSMC dedifferentiation in vitro. Smooth muscle cells specific Gls1 knockout (Gls1SMKO) mice exhibited aggravated AD upon BAPN treatment, whereas VSMCs specific GLS1 overexpression improved the contractile phenotype and reduced AD incidence. Mechanistically, GLS1 downregulation impaired glutamate metabolism, leading to reduced levels of glutathione and α-ketoglutarate. This metabolic disruption promoted reactive oxygen species accumulation and mitochondrial dysfunction, ultimately triggering VSMC phenotypic switching. Furthermore, we found that GLS1 transcription was repressed by retinoic acid receptor-α (RARα). Pharmacologic inhibition of RARα with AR7 restored GLS1 expression, ameliorated VSMC phenotypic switching, and conferred protection against AD. These findings reveal a critical role of GLS1-mediated glutamate metabolism in VSMC phenotypic switching and suggest a promising therapeutic strategy for AD.
Authors
Wei Xie, Chen Ning, Chen Lu, Dongjin Wang, Shuang Zhao, Tianyu Song, Hailong Cao
Abstract
Chronic hyperglycemia induces microvascular complications in patients with type 2 diabetes (T2D), particularly diabetic retinopathy, nephropathy, and neuropathy. We revisited to examine such vascular damage in the pancreas in 3D. Using thick pancreatic tissue slices, we analyzed volumetric intraislet and peri-islet exocrine capillary density (vICD and vECD), as well as interface capillary counts along the islet periphery to quantify vascular integration between the islets and surrounding acinar cells. Contrary to the previous reports, vICD was not homogeneous, but highly heterogeneous across the five species studied (human, monkey, pig, ferret and mouse), especially in smaller islets (15%–80%). vICD became less variable with increasing islet size converging at approximately 20%. With this foundation of islet vascularization, pancreatic tissues from non-diabetic (ND) and T2D subjects consisting of eight age- and sex-matched pairs (age range of 35-65 years with various duration: 0-15 years) were examined. Strikingly, no significant differences in microvasculature were found, where mean vICD (~30%) and mean vECD (~15%) were nearly equivalent between the groups. Capillary integration with respect to islet size was comparable. It suggests that integrated pancreatic blood flow with robust crosstalk between the endocrine and exocrine pancreas may facilitate microvascular preservation in T2D via local distribution of insulin.
Authors
Alex M. Tollefson, Frank R. Marsico, Manami Hara
Abstract
We generated a comparative spatial proteomic atlas of the human and mouse retina using a highly multiplexed immunohistochemistry technique called iterative bleaching extends multiplexity (IBEX). We refined the IBEX workflow by integrating an antibody dissociation option alongside chemical bleaching. This dual strategy enabled removal of the entire antibody complex, permitting the flexible use of antibodies from the same host species across iterative cycles. We coupled this workflow with super-resolution imaging via deconvolution and applied it to the retina of healthy humans and WT mice and the Crb1rd8 mouse model. We successfully imaged over 25 protein markers on human and mouse tissue sections, generating spatial atlases of the major retinal cell populations. Cross-species protein expression was compared to scRNA-seq datasets to identify protein and transcript disparities. Super-resolution IBEX delineated the ultrastructural features of the outer limiting membrane (OLM), identifying CD44 as a core structural component tightly colocalized with a highly organized F-actin belt within Müller glial endfeet. Using the Crb1rd8 mouse model, disruption of this complex was spatially associated with rosette formation and OLM structural failure. In summary, spatial proteomic atlases of the human and mouse retina were used to reveal insights into the arrangement of major retinal cell populations and OLM structure.
Authors
Yuxuan Meng, Jakub Kubiak, Zuzanna Dzieniak, Lorna Fowler, Rose Avient, Jason Hopley, Linyulong Li, Chaoran Li, Yuan Tian, Bruno Charbit, Colin J. Chu
Abstract
Vascularized skins were 3D printed using single donor human fibroblasts, pericytes, keratinocytes, and endothelial cells (ECs), the latter either unmodified (WT-ECs) or deleted of MHC molecules (KO-ECs). Adult MISTRG6 immunodeficient mice neonatally inoculated with adult human hematopoietic stem cells (HSCs) received printed skin allogeneic to the HSCs and were boosted 3 weeks after grafting with human PBMCs autologous to the HSCs. HSC inoculation alone produced low levels of circulating human myeloid and lymphoid cells without affecting grafts; PBMC boosting dramatically increased circulating human CD4+ T cells and boosted CD8+ T cells only in mice with WT-EC grafts. These grafts became infiltrated by human macrophages, dendritic cells, CD4+ and CD8+ T cells and showed evidence of rejection. Shared T cell clones were present in skin and spleen. KO-EC grafts had minimal infiltration of graft or spleen without rejection, despite MHC molecule expression on other graft cell types.
Authors
Zuzana Tobiasova, Esen Sefik, Lingfeng Qin, Jennifer M. McNiff, Gwendolyn Davis, Richard A. Flavell, W. Mark Saltzman, Jordan S. Pober
Abstract
Systemic sclerosis (SSc) is characterized by fibrosis and vasculopathy affecting the skin and internal organs, leading to multiorgan dysfunction. Injury of microvascular endothelial cells (ECs) in SSc impairs blood flow and causes tissue ischemia, leading to vascular complications such as Raynaud’s, digital ulcers, and pulmonary hypertension (PH). PH in SSc presents as group 1 pulmonary arterial hypertension or as group 3 PH related to hypoxia and interstitial lung disease (ILD), both major causes of mortality. Analysis of multiome data from SSc ILD-PH lungs inferred transcription factors regulating EC phenotype, including FOSL2. Overexpression of FOSL2 in transgenic mice (Fosl2tg) leads to vascular changes mirroring human SSc-PH, such as intimal thickening and fibrosis. scRNA-Seq analysis of altered EC gene expression in Fosl2tg mice showed strong overlap with altered EC gene expression in SSc-ILD-PH. Overlapping as well as discrete EC gene expression in Sugen/hypoxia- and hypoxia-treated mice suggested that FOSL2 regulates both hypoxia-dependent and -independent pathways in Fosl2tg mice and SSc-ILD-PH. A deep learning model, ChromBPNet, inferred increased AP-1 binding at base pair resolution in SSc-ILD-PH ECs, and binding to the same motifs was found upon FOSL2 overexpression in primary vascular ECs, highlighting FOSL2’s key role in driving the pathological changes seen in SSc-ILD-PH.
Authors
Rithika Behera, Yuechen Zhou, Peter H. Gerges, Jingyu Fan, Tracy Tabib, Alyxzandria M. Gaydosik, Mengqi Huang, Jishnu Das, Elena Pachera, Amela Hukara, Ying Tang, Florian Renoux, Miranda Tai, Oliver Distler, Gabriela Kania, Stephen Y. Chan, Harinder Singh, Eleanor Valenzi, Robert Lafyatis
Abstract
Interscapular brown adipose tissue (iBAT), one of the most vascularized tissues in the body, exemplifies the intricate crosstalk between the vascular system and adipocytes. BAT is known to secrete abundant exosomes into circulation, while exosomes are known to play a key role in vascular remodeling and cell migration. However, whether BAT-derived exosomes (BATexos) modulate peripheral vasculature remains unclear. Here, we report that BATexos promoted peripheral angiogenesis and vascular repair. Among their cargo, miR-378a-3p was highly enriched and identified as a key mediator of endothelial angiogenic function. The overexpression of miR-378a-3p in endothelial cells substantially promoted cell migration and tube formation. Conversely, inhibition of exosome secretion from BAT impaired vascular repair and delayed wound healing. Mechanistically, miR-378a-3p directly targeted the phosphatase and tensin homolog (Pten), thereby activating the PI3K-AKT signaling pathway. Liposomes encapsulating miR-378 mimics promoted angiogenesis and accelerated wound healing in a diabetic mouse model. Collectively, this study uncovers BAT-derived miR-378a-3p as a key regulator of vessel regeneration and tissue repair following injury, offering new therapeutic potential for treating vascular complications in metabolic disease.
Authors
Hongyan Deng, Yuyu Xie, Jiadai Liu, Jing Ge, Qianqian Kang, Rui He, Zhihan Wang, Xuemin Peng, Zengzhe Zhu, Wenshe Wang, Yulian Liu, Ronghui Gao, Ruping Pan, Min Yang, Yong Chen
Abstract
Giant cell aortitis (GCA) is an inflammatory disease of the aortic wall with a characteristic giant cell pattern on pathology and can lead to life-threatening aortic aneurysm and dissection. Pathogenic GCA mechanisms underlying aortic inflammation and persistence remain elusive. Here, we demonstrate the complexity of medial layer destruction and immune cell infiltration in clinical granulomatous GCA and lymphoplasmacytic IgG4-related aortitis samples using imaging-based gene expression profiling. Single-cell spatial profiling revealed aortic wall remodeling in the GCA aortas, highlighting substantial phenotypic modulation in stromal cells, including vascular smooth muscle cells (SMCs) and fibroblasts. Specifically, we observed the expansion of stromal cells expressing Tenascin-C (TNC) mRNA and spatially refined TNC accumulation in lesion areas. We confirmed these findings histologically using diseased aortas resected from individuals with giant cell arteritis and clinically isolated aortitis. Mechanistically, our data suggest that TNC promotes a proinflammatory phenotype in primary human SMCs, elevating IL-6 levels partially through the TLR4/NF-κB pathway. IL-6 signaling propagates the proinflammatory loop by activating STAT3. Pharmacological blockade of the IL-6 receptor using tocilizumab alleviated the TNC-driven proinflammatory phenotype. We propose that TNC acts as a local catalyst of inflammatory disease persistence mainly via IL-6 signaling activation and offers a potential avenue for sustained disease remission.
Authors
Hui Shi, Ying Tang, Jing Li, Ora Gewurz-Singer, Bo Yang, Dogukan Mizrak
No posts were found with this tag.
