A unifying concept in vascular health and disease Schwartz, Martin A; Vestweber, Dietmar; Simons, Michael
Science (American Association for the Advancement of Science),
2018-Apr-20, 2018-04-20, 20180420, Volume:
360, Issue:
6386
Journal Article
Peer reviewed
Open access
Interventions to restore blood vessel stability could improve health outcomes
Not unlike Tolstoy's remark about happy versus unhappy families, current wisdom in vascular biology holds that healthy ...blood vessels are mostly similar, whereas vessels in different vascular diseases are mostly different. But is this really the case? An evaluation of the literature suggests that unresolved vascular remodeling may be a key element of virtually all vascular diseases. This commonality raises the possibility of unifying principles that govern vascular remodeling and the possibility that methods to restore normal remodeling could effectively treat multiple disease states.
Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis ...(blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.
The vertebrate vasculature forms an extensive branched network of blood vessels that supplies tissues with nutrients and oxygen. During vascular development, coordinated control of endothelial cell ...behaviour at the levels of cell migration, proliferation, polarity, differentiation and cell-cell communication is critical for functional blood vessel morphogenesis. Recent data uncover elaborate transcriptional, post-transcriptional and post-translational mechanisms that fine-tune key signalling pathways (such as the vascular endothelial growth factor and Notch pathways) to control endothelial cell behaviour during blood vessel sprouting (angiogenesis). These emerging frameworks controlling angiogenesis provide unique insights into fundamental biological processes common to other systems, such as tissue branching morphogenesis, mechanotransduction and tubulogenesis.
Free-form fabrication techniques, often referred to as ‘3D printing’, are currently tested with regard to the processing of biological and biocompatible materials in general and for fabrication of ...vessel-like structures in particular. Such computer-controlled methods assemble 3D objects by layer-wise deposition or layer-wise cross-linking of materials. They use, for example, nozzle-based deposition of hydrogels and cells, drop-on-demand inkjet-printing of cell suspensions with subsequent cross-linking, layer-by-layer cross-linking of synthetic or biological polymers by selective irradiation with light and even laser-induced deposition of single cells. The need of vessel-like structures has become increasingly crucial for the supply of encapsulated cells for 3D tissue engineering, or even with regard to future application such as vascular grafts. The anticipated potential of providing tubes with tailored branching geometries made of biocompatible or biological materials pushes future visions of patient-specific vascularized tissue substitutions, tissue-engineered blood vessels and bio-based vascular grafts. We review here the early attempts of bringing together innovative free-form manufacturing processes with bio-based and biodegradable materials. The presented studies provide many important proofs of concepts such as the possibility to integrate viable cells into computer-controlled processes and the feasibility of supplying cells in a hydrogel matrix by generation of a network of perfused channels. Several impressive results in the generation of complex shapes and high-aspect-ratio tubular structures demonstrate the potential of additive assembly methods. Yet, it also becomes obvious that there remain major challenges to simultaneously match all material requirements in terms of biological functions (cell function supporting properties), physicochemical functions (mechanical properties of the printed material) and process-related (viscosity, cross-linkability) functions, towards the demanding goal of biofabricating artificial blood vessels.
The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-γ (IFNγ) is critical in most of the analysed models. Although IFNγ can impede ...tumour growth by acting directly on cancer cells, it must also act on the tumour stroma for effective rejection of large, established tumours. However, which stroma cells respond to IFNγ and by which mechanism IFNγ contributes to tumour rejection through stromal targeting have remained unknown. Here we use a model of IFNγ induction and an IFNγ-GFP fusion protein in large, vascularized tumours growing in mice that express the IFNγ receptor exclusively in defined cell types. Responsiveness to IFNγ by myeloid cells and other haematopoietic cells, including T cells or fibroblasts, was not sufficient for IFNγ-induced tumour regression, whereas responsiveness of endothelial cells to IFNγ was necessary and sufficient. Intravital microscopy revealed IFNγ-induced regression of the tumour vasculature, resulting in arrest of blood flow and subsequent collapse of tumours, similar to non-haemorrhagic necrosis in ischaemia and unlike haemorrhagic necrosis induced by tumour necrosis factor. The early events of IFNγ-induced tumour ischaemia resemble non-apoptotic blood vessel regression during development, wound healing or IFNγ-mediated, pregnancy-induced remodelling of uterine arteries. A better mechanistic understanding of how solid tumours are rejected may aid the design of more effective protocols for adoptive T-cell therapy.
The glycocalyx: a central regulator of vascular function Moore, Kyle H; Murphy, Hayley A; George, Eric M
American journal of physiology. Regulatory, integrative and comparative physiology,
04/2021, Volume:
320, Issue:
4
Journal Article
Peer reviewed
Open access
The endothelial glycocalyx is a specialized extracellular matrix that covers the apical side of vascular endothelial cells, projecting into the lumen of blood vessels. The composition of the ...glycocalyx has been studied in great detail, and it is known to be composed of a mixture of proteoglycans, glycosaminoglycans, and glycoproteins. Although this structure was once believed to be a passive physical barrier, it is now recognized as a multifunctional and dynamic structure that participates in many vascular processes, including but not limited to vascular permeability, inflammation, thrombosis, mechanotransduction, and cytokine signaling. Because of its participation in many physiological and pathophysiological states, comprehensive knowledge of the glycocalyx will aid future vascular biologists in their research. With that in mind, this review discusses the biochemical structure of the glycocalyx and its function in many vascular physiological processes. We also briefly review a more recent discovery in glycocalyx biology, the placental glycocalyx.
The process of implantation and the cellular interactions at the embryo-maternal interface are intrinsically difficult to analyze, as the implanting embryo is concealed by the uterine tissues. ...Therefore, the mechanisms mediating the interconnection of the embryo and the mother are poorly understood. Here, we established a 3D biomimetic culture environment that harbors the key features of the murine implantation niche. This culture system enabled direct analysis of trophoblast invasion and revealed the first embryonic interactions with the maternal vasculature. We found that implantation is mediated by the collective migration of penetrating strands of trophoblast giant cells, which acquire the expression of vascular receptors, ligands, and adhesion molecules, assembling a network for communication with the maternal blood vessels. In particular, Pdgf signaling cues promote the establishment of the heterologous contacts. Together, the biomimetic platform and our findings thereof elucidate the hidden dynamics of the early interactions at the implantation site.
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•3D biomimetic culture environment, harboring key features of the implantation niche•Implantation is mediated by collective migration of penetrating trophoblast strands•TGCs acquire vascular gene expression for communication with the maternal vasculature•Pdgf signaling cues promote the establishment of heterologous contacts
The cellular mechanisms underlying embryo-maternal interactions during implantation are poorly understood, as the implantation site is concealed by the uterine tissues. Here, Govindasamy et al. established a 3D biomimetic environment that enables direct analysis of the implantation process, revealing the first embryonic interactions with the maternal vasculature.
Angiogenesis is the generation of mature vascular networks from pre-existing vessels. Angiogenesis is crucial during the organism' development, for wound healing and for the female reproductive ...cycle. Several murine experimental systems are well suited for studying developmental and pathological angiogenesis. They include the embryonic hindbrain, the post-natal retina and allantois explants. In these systems vascular networks are visualised by appropriate staining procedures followed by microscopical analysis. Nevertheless, quantitative assessment of angiogenesis is hampered by the lack of readily available, standardized metrics and software analysis tools. Non-automated protocols are being used widely and they are, in general, time--and labour intensive, prone to human error and do not permit computation of complex spatial metrics. We have developed a light-weight, user friendly software, AngioTool, which allows for quick, hands-off and reproducible quantification of vascular networks in microscopic images. AngioTool computes several morphological and spatial parameters including the area covered by a vascular network, the number of vessels, vessel length, vascular density and lacunarity. In addition, AngioTool calculates the so-called "branching index" (branch points/unit area), providing a measurement of the sprouting activity of a specimen of interest. We have validated AngioTool using images of embryonic murine hindbrains, post-natal retinas and allantois explants. AngioTool is open source and can be downloaded free of charge.
Endothelial cell heterogeneity in forming new blood vessels
Abstract
The vast blood-vessel network of the circulatory system is crucial for maintaining bodily homeostasis, delivering essential ...molecules and blood cells, and removing waste products. Blood-vessel dysfunction and dysregulation of new blood-vessel formation are related to the onset and progression of many diseases including cancer, ischemic disease, inflammation and immune disorders. Endothelial cells (ECs) are fundamental components of blood vessels and their proliferation is essential for new vessel formation, making them good therapeutic targets for regulating the latter. New blood-vessel formation occurs by vasculogenesis and angiogenesis during development. Induction of ECs termed tip, stalk and phalanx cells by interactions between vascular endothelial growth factor A (VEGF-A) and its receptors (VEGFR1–3) and between Notch and Delta-like Notch ligands (DLLs) is crucial for regulation of angiogenesis. Although the importance of angiogenesis is unequivocal in the adult, vasculogenesis effected by endothelial progenitor cells (EPCs) may also contribute to post-natal vessel formation. However, the definition of these cells is ambiguous and they include several distinct cell types under the simple classification of ‘EPC’. Furthermore, recent evidence indicates that ECs within the intima show clonal expansion in some situations and that they may harbor vascular-resident endothelial stem cells. In this article, we summarize recent knowledge on vascular development and new blood-vessel formation in the adult. We also introduce concepts of EC heterogeneity and EC clonal expansion, referring to our own recent findings.
Met tyrosine kinase receptor, also known as c-Met, is the HGF (hepatocyte growth factor) receptor. The HGF/Met pathway has a prominent role in cardiovascular remodelling after tissue injury. The ...present review provides a synopsis of the cellular and molecular mechanisms underlying the effects of HGF/Met in the heart and blood vessels. In vivo, HGF/Met function is particularly important for the protection of the heart in response to both acute and chronic insults, including ischaemic injury and doxorubicin-induced cardiotoxicity. Accordingly, conditional deletion of Met in cardiomyocytes results in impaired organ defence against oxidative stress. After ischaemic injury, activation of Met provides strong anti-apoptotic stimuli for cardiomyocytes through PI3K (phosphoinositide 3-kinase)/Akt and MAPK (mitogen-activated protein kinase) cascades. Recently, we found that HGF/Met is also important for autophagy regulation in cardiomyocytes via the mTOR (mammalian target of rapamycin) pathway. HGF/Met induces proliferation and migration of endothelial cells through Rac1 (Ras-related C3 botulinum toxin substrate 1) activation. In fibroblasts, HGF/Met antagonizes the actions of TGFβ1 (transforming growth factor β1) and AngII (angiotensin II), thus preventing fibrosis. Moreover, HGF/Met influences the inflammatory response of macrophages and the immune response of dendritic cells, indicating its protective function against atherosclerotic and autoimmune diseases. The HGF/Met axis also plays an important role in regulating self-renewal and myocardial regeneration through the enhancement of cardiac progenitor cells. HGF/Met has beneficial effects against myocardial infarction and endothelial dysfunction: the cellular and molecular mechanisms underlying repair function in the heart and blood vessels are common and include pro-angiogenic, anti-inflammatory and anti-fibrotic actions. Thus administration of HGF or HGF mimetics may represent a promising therapeutic agent for the treatment of both coronary and peripheral artery disease.
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