The role of inflammation in cardiovascular disease (CVD) is now widely accepted. Immune cells, including T cells, are influenced by inflammatory signals and contribute to the onset and progression of ...CVD. T cell activation is modulated by T cell co-stimulation and co-inhibition pathways. Immune checkpoint inhibitors (ICIs) targeting T cell inhibition pathways have revolutionized cancer treatment and improved survival in patients with cancer. However, ICIs might induce cardiovascular toxicity via T cell re-invigoration. With the rising use of ICIs for cancer treatment, a timely overview of the role of T cell co-stimulation and inhibition molecules in CVD is desirable. In this Review, the importance of these molecules in the pathogenesis of CVD is highlighted in preclinical studies on models of CVD such as vein graft disease, myocarditis, graft arterial disease, post-ischaemic neovascularization and atherosclerosis. This Review also discusses the therapeutic potential of targeting T cell co-stimulation and inhibition pathways to treat CVD, as well as the possible cardiovascular benefits and adverse events after treatment. Finally, the Review emphasizes that patients with cancer who are treated with ICIs should be monitored for CVD given the reported association between the use of ICIs and the risk of cardiovascular toxicity.
Mouse hind limb ischemia is the most common used preclinical model for peripheral arterial disease and critical limb ischemia. This model is used to investigate the mechanisms of neovascularization ...and to develop new therapeutic agents. The literature shows many variations in the model, including the method of occlusion, the number of occlusions, and the position at which the occlusions are made to induce hind limb ischemia. Furthermore, predefined end points and the histopathological and radiological analysis vary. These differences hamper the correlation of results between different studies. In this review, variations in surgical methods of inducing hind limb ischemia in mice are described, and the consequences of these variations on perfusion restoration and vascular remodeling are discussed. This study aims at providing the reader with a comprehensive overview of the methods so far described, and proposing uniformity in research of hind limb ischemia in a mouse model.
The review discusses the recent literature on plaque angiogenesis and its relation to inflammation and plaque destabilization. Furthermore, it discusses how plaque angiogenesis can be used to monitor ...atherosclerosis and serve as a therapeutic target.
Histopathologic studies have shown a clear relationship between plaque angiogenesis, intraplaque hemorrhage (IPH), plaque vulnerability, and cardiovascular events. Hypoxia is a main driver of plaque angiogenesis and the mechanism behind angiogenesis is only partly known. IPH, as the result of immature neovessels, is associated with increased influx of inflammatory cells in the plaques. Experimental models displaying certain features of human atherosclerosis such as plaque angiogenesis or IPH are developed and can contribute to unraveling the mechanism behind plaque vulnerability. New imaging techniques are established, with which plaque angiogenesis and vulnerability can be detected. Furthermore, antiangiogenic therapies in atherosclerosis gain much attention.
Plaque angiogenesis, IPH, and inflammation contribute to plaque vulnerability. Histopathologic and imaging studies together with specific experimental studies have provided insights in plaque angiogenesis and plaque vulnerability. However, more extensive knowledge on the underlying mechanism is required for establishing new therapies for patients at risk.
C-X-C motif ligand 10 (CXCL10), or interferon-inducible protein-10, is a small chemokine belonging to the CXC chemokine family. Its members are responsible for leukocyte trafficking and act on tissue ...cells, like endothelial and vascular smooth muscle cells. CXCL10 is secreted by leukocytes and tissue cells and functions as a chemoattractant, mainly for lymphocytes. After binding to its receptor CXCR3, CXCL10 evokes a range of inflammatory responses: key features in cardiovascular disease (CVD). The role of CXCL10 in CVD has been extensively described, for example for atherosclerosis, aneurysm formation, and myocardial infarction. However, there seems to be a discrepancy between experimental and clinical settings. This discrepancy occurs from differences in biological actions between species (e.g. mice and human), which is dependent on CXCL10 signaling via different CXCR3 isoforms or CXCR3-independent signaling. This makes translation from experimental to clinical settings challenging. Furthermore, the overall consensus on the actions of CXCL10 in specific CVD models is not yet reached. The purpose of this review is to describe the functions of CXCL10 in different CVDs in both experimental and clinical settings and to highlight and discuss the possible discrepancies and translational difficulties. Furthermore, CXCL10 as a possible biomarker in CVD will be discussed.
Acute cardiovascular events, due to rupture or erosion of an atherosclerotic plaque, represent the major cause of morbidity and mortality in patients. Growing evidence suggests that plaque ...neovascularization is an important contributor to plaque growth and instability. The vessels’ immaturity, with profound structural and functional abnormalities, leads to recurrent intraplaque hemorrhage.
This review discusses new insights of atherosclerotic neovascularization, including the effects of leaky neovessels on intraplaque hemorrhage, both in experimental models and humans. Furthermore, modalities for in vivo imaging and therapeutic interventions to target plaque angiogenesis will be discussed.
Significant progress has been made in the clinical management of a variety of cardiovascular diseases. Nevertheless, the therapeutic efficacy of the current treatment modalities for atherosclerosis ...and restenosis is not fully sufficient in a large proportion of patients. One of the major contributing factors is the clinical and biological heterogeneity of these still life-threatening diseases, which involve processes that we do not fully understand at the moment. Over the past decades, it has become increasingly clear that part of the gene–environmental interactions relevant for complex diseases is regulated by epigenetic mechanisms such as histone acetylation and DNA methylation. Epigenetic processes modulate gene expression patterns without modifying the actual DNA sequence and have profound effects on the cellular repertoire of expressed genes. They contribute to the expression of genes that play a key role in extracellular matrix formation, inflammation, and proliferation, processes involved in cardiovascular pathologies such as atherosclerosis and restenosis. Therefore, in this review, we argue that epigenetic regulators involved in histone acetylating and deacetylating activities contribute to the pathogenesis of atherosclerosis and restenosis. Furthermore, as alterations in chromatin structure are reversible, these epigenetic modifications are amendable to pharmacological intervention, which may prove to be an effective treatment modality for the management of cardiovascular diseases.
Cell therapies involving the administration of bone marrow-derived mononuclear cells (BM-MNCs) for patients with chronic limb-threatening ischemia (CLTI) have shown promise; however, their overall ...effectiveness lacks evidence, and the exact mechanism of action remains unclear. In this study, we examined the angiogenic effects of well-controlled human bone marrow cell isolates on endothelial cells. The responses of endothelial cell proliferation, migration, tube formation, and aortic ring sprouting were analyzed in vitro, considering both the direct and paracrine effects of BM cell isolates. Furthermore, we conducted these investigations under both normoxic and hypoxic conditions to simulate the ischemic environment. Interestingly, no significant effect on the angiogenic response of human umbilical vein endothelial cells (HUVECs) following treatment with BM-MNCs was observed. This study fails to provide significant evidence for angiogenic effects from human bone marrow cell isolates on human endothelial cells. These in vitro experiments suggest that the potential benefits of BM-MNC therapy for CLTI patients may not involve endothelial cell angiogenesis.
MicroRNAs are posttranscriptional regulators of gene expression. As microRNAs can target many genes simultaneously, microRNAs can regulate complex multifactorial processes, including post-ischemic ...neovascularization, a major recovery pathway in cardiovascular disease. MicroRNAs select their target mRNAs via full complementary binding with their seed sequence, i.e., nucleotides 2–8 from the 5′ end of a microRNA. The exact sequence of a mature microRNA, and thus of its 5′ and 3′ ends, is determined by two sequential cleavage steps of microRNA precursors, Drosha/DGCR8 and Dicer. When these cleavage steps result in nucleotide switches at the 5′ end, forming a so-called 5′-isomiR, this results in a shift in the mature microRNA’s seed sequence. The role of 5′-isomiRs in cardiovascular diseases is still unknown. Here, we characterize the expression and function of the 5′-isomiR of miR-411 (ISO-miR-411). ISO-miR-411 is abundantly expressed in human primary vascular cells. ISO-miR-411 has a different “targetome” from WT-miR-411, with only minor overlap. The ISO-miR-411/WT-miR-411 ratio is downregulated under acute ischemia, both in cells and a murine ischemia model, but is upregulated instead in chronically ischemic human blood vessels. ISO-miR-411 negatively influences vascular cell migration, whereas WT-miR-411 does not. Our data demonstrate that isomiR formation is a functional pathway that is actively regulated during ischemia.
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The function and regulation of individual microRNAs sequence variants (isomiRs) are largely unknown. van der Kwast and colleagues report that miR-411’s 5′-isomiR is abundantly expressed in the vasculature and differentially regulated under ischemia. IsomiR-411 has a unique target set and anti-angiogenic properties, suggesting that isomiRs play a functional role in the vasculature.
Pericellular proteases play an important role in angiogenesis and vasculogenesis. They comprise (membrane-type) matrix metalloproteinases (MT-)MMPs, serine proteases, cysteine cathepsins, and ...membrane-bound aminopeptidases. Specific inhibitors regulate them. Major roles in initiating angiogenesis have been attributed to MT1-matrix metalloproteinase (MMP), MMP-2, and MMP-9. Whereas MT-MMPs are membrane-bound by nature, MMP-2 and MMP-9 can localize to the membrane by binding to alphavbeta3-integrin and CD44, respectively. Proteases switch on neovascularization by activation, liberation, and modification of angiogenic growth factors and degradation of the endothelial and interstitial matrix. They also modify the properties of angiogenic growth factors and cytokines. Neovascularization requires cell migration, which depends on the assembly of protease-protein complexes at the migrating cell front. MT1-MMP and urokinase (u-PA) form multiprotein complexes in the lamellipodia and focal adhesions of migrating cells, facilitating proteolysis and sufficient support for endothelial cell migration and survival. Excessive proteolysis causes loss of endothelial cell-matrix interaction and impairs angiogenesis. MMP-9 and cathepsin L stimulate the recruitment and action of blood- or bone-marrow-derived accessory cells that enhance angiogenesis. Proteases also generate fragments of extracellular matrix and hemostasis factors that have anti-angiogenic properties. Understanding the complexity of protease activities in angiogenesis contributes to recognizing new targets for stimulation or inhibition of neovascularization in disease.
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