Fig 1 - uploaded by Jesús Torres-Vázquez
Content may be subject to copyright.
Arteries and veins. Arteries and veins are both com- posed of an inner endothelium (tunica intima) surrounded by internal elastic tissue, smooth muscle cell layer (tunica media), external elastic tissue, and fibrous connective tissue (tunica adventitia). Larger caliber arteries have thicker smooth muscle cell layers while larger veins possess specialized structures such as valves. The two networks of tubes are completely separate at the level of the larger vessels but are linked together distally, in a system of fine capillaries found throughout all tissues, as well as proximally, at the heart. Reproduced from Cleaver and Krieg (1999), with permission
Source publication
The vertebrate vascular system is essential for the delivery and exchange of gases, hormones, metabolic wastes and immunity factors. These essential functions are carried out in large part by two types of anatomically distinct blood vessels, namely arteries and veins. Previously, circulatory dynamics were thought to play a major role in establishin...
Context in source publication
Context 1
... distal sites within the body. The proper functioning of the circulatory system as a closed loop continually recirculating blood to and from periph- eral tissues is itself dependent on the fundamental structural dichotomy of this system. The vasculature is divided into two largely distinct and separate networks of arterial and venous blood vessels (Fig. 1). While the existence of these two fundamental types of blood vessels and their distinct roles have been appreciated for hundreds if not thousands of years, we have only begun to understand the functional and molecular differences between the cells that line these two types of vessels, not to mention how these differences are acquired. ...
Similar publications
Tubular sprouting in angiogenesis relies on division of labour between endothelial tip cells, leading and guiding the sprout, and their neighboring stalk cells, which divide and form the vascular lumen. We previously learned how the graded extracellular distribution of heparin-binding vascular endothelial growth factor (VEGF)-A orchestrates and bal...
Citations
... In mice, embryonic vasculatures arise simultaneously in embryonic and extraembryonic tissues via vasculogenesis, a process of de novo blood vessel formation (Drake and Fleming, 2000;Chong et al., 2011). After that, BECs respond to angiogenic growth factors, sprouting from pre-existing vessels by angiogenesis (Majesky, 2018) and undergo specialization into venous or arterial BECs before the formation of mature vasculature by diverse factors, such as hemodynamic forces and transcriptional programs (Jain, 2003;Heil et al., 2006;Lin, 2007) After arterial or venous BEC fate is determined, each BEC expresses distinct sets of transcriptomes and displays different branching capacities (Jain, 2003;Torres-Vazquez et al., 2003). Following the maturation of blood vessels, some of the venous ECs in the anterior part of the cardinal vein (CV) express Prox1, Lyve1, and Sox18, and differentiation to lymphatic EC (LECs) begins at approximately embryonic day (E) 9-10 in mice (Tammela and Alitalo, 2010;Potente and Makinen, 2017). ...
Epigenetic mechanisms are mandatory for endothelial called lymphangioblasts during cardiovascular development. Dot1l-mediated gene transcription in mice is essential for the development and function of lymphatic ECs (LECs). The role of Dot1l in the development and function of blood ECs blood endothelial cells is unclear. RNA-seq datasets from Dot1l-depleted or -overexpressing BECs and LECs were used to comprehensively analyze regulatory networks of gene transcription and pathways. Dot1l depletion in BECs changed the expression of genes involved in cell-to-cell adhesion and immunity-related biological processes. Dot1l overexpression modified the expression of genes involved in different types of cell-to-cell adhesion and angiogenesis-related biological processes. Genes involved in specific tissue development-related biological pathways were altered in Dot1l-depleted BECs and LECs. Dot1l overexpression altered ion transportation-related genes in BECs and immune response regulation-related genes in LECs. Importantly, Dot1l overexpression in BECs led to the expression of genes related to the angiogenesis and increased expression of MAPK signaling pathways related was found in both Dot1l-overexpressing BECs and LECs. Therefore, our integrated analyses of transcriptomics in Dot1l-depleted and Dot1l-overexpressed ECs demonstrate the unique transcriptomic program of ECs and the differential functions of Dot1l in the regulation of gene transcription in BECs and LECs.
... Patterns of DLL4 expression are regulated by SOXF (e.g., SOX7, SOX17, SOX18), ETS (e.g., ETS1) and RBPJ transcription factor gene families [75][76][77]. The intersection of multiple additional signaling pathways, including VEGF, MAPK/ERK, Hedgehog, WNT/β-catenin and blood flow-induced nitric oxide (NO) [78][79][80], are also implicated in the control of arterial fate specification at this stage of development (reviewed in [81,82]) ( Figure 2). ...
The ability to manufacture human hematopoietic stem cells (HSCs) in the laboratory holds enormous promise for cellular therapy of human blood diseases. Several differentiation protocols have been developed to facilitate the emergence of HSCs from human pluripotent stem cells (PSCs). Most approaches employ a stepwise addition of cytokines and morphogens to recapitulate the natural developmental process. However, these protocols globally lack clinical relevance and uniformly induce PSCs to produce hematopoietic progenitors with embryonic features and limited engraftment and differentiation capabilities. This review examines how key intrinsic cues and extrinsic environmental inputs have been integrated within human PSC differentiation protocols to enhance the emergence of definitive hematopoiesis and how advances in genomics set the stage for imminent breakthroughs in this field.
... On the other hand, the development of the zebrafish dorsal aorta involves individual cell migration ( Figure I.3 B). Cells that will form the dorsal aorta originate from the lateral plate mesoderm [Torres-Vázquez et al., 2003]. These cells detach from the lateral plate mesoderm through an epithelial to mesenchymal transition process (EMT) [Poole et al., 2001]. ...
Dorsal closure and head involution are among the last major events in the morphogenesisof the Drosophila melanogaster embryo, taking place during stages 13 to 15. During dorsal closure, the cells of the dorsal epidermis elongate until they fusewith their counterparts on the dorsal midline, pulled by an extra-embryonic tissue:the amnioserosa. At the same time, the dorsal epidermis of the thoracic segments,having just fused, covers the head of the embryo: that is the head involution . I dedicated this thesis to the understanding of the morphogenetic processes at the origin of these two phenomena and to their regulation by two signaling pathways:JNK and DPP (the TGFβ homolog in D. melanogaster ). [...] Finally, I identify how a subpopulation of cells from the head epidermis participatein the migration of the thoracic epidermis over it. These cells are organized in twobands located laterally on either side of the head epidermis. During head involution,these two bands contract thanks to the intercalation of their cells as well as the reduction of their apical area. Thus, these bands act as suspenders pulling on the thoracic epidermis via the dorsal ridge. Concomitantly, the dorsal ridge also contracts and acts as a belt to synchronize the migration of the thoracic epidermis over the head. Altogether, this work demonstrates that the role of the DPP pathwayin the regulation of late epidermal morphogenesis in the Drosophila embryooriginates much earlier than previously thought. It also sheds light on the crucialrole of inter-organ cooperation during this process.
... In zebrafish embryos, arterial specification is mainly controlled by vascular endothelial growth factor (Vegf) activating Notch signals via PLC-r-PKC-MEK pathways [13][14][15][16]. Venous cells expressing different markers indicated a distinct genetic regulation via PI3K/AKT signaling in angioblasts to enhance vein specification [17,18]. However, the precise mechanism of signaling interactions during vasculogenesis is not fully understood. ...
The genetic regulation of vascular development is not elucidated completely. We previously characterized the transcription factors Islet2 (Isl2) and Nr2f1b as being critical for vascular growth. In this study, we further performed combinatorial microarrays to identify genes that are potentially regulated by these factors. We verified the changed expression of several targets in isl2/nr2f1b morphants. Those genes expressed in vessels during embryogenesis suggested their functions in vascular development. We selectively assayed a potential target follistatin a (fsta). Follistatin is known to inhibit BMP, and BMP signaling has been shown to be important for angiogenesis. However, the fsta’s role in vascular development has not been well studied. Here, we showed the vascular defects in ISV growth and CVP patterning while overexpressing fsta in the embryo, which mimics the phenotype of isl2/nr2f1b morphants. The vascular abnormalities are likely caused by defects in migration and proliferation. We further observed the altered expression of vessel markers consistent with the vascular defects in (fli:fsta) embryos. We showed that the knockdown of fsta can rescue the vascular defects in (fli:fsta) fish, suggesting the functional specificity of fsta. Moreover, the decreased expression of fsta rescues abnormal vessel growth in isl2 and nr2f1b morphants, indicating that fsta functions downstream of isl2/nr2f1b. Lastly, we showed that Isl2/Nr2f1b control vascular development, via Fsta–BMP signaling in part. Collectively, our microarray data identify many interesting genes regulated by isl2/nr2f1b, which likely function in the vasculature. Our research provides useful information on the genetic control of vascular development.
... Furthermore, the NOTCH pathway is one of the main drivers of endothelial cellTorres-Vázquez et al., 2003). Although NOTCH signalling dynamics have been studied in HUVEC and retina, it is still unclear how it affects EC heterogeneity in different organs.Nuclear NOTCH1 (N1-ICD) acts as a transcription co-factor to induce the expression of target genes such as the HES/HEY family of transcription factors and is therefore active in the nucleus. ...
Endothelial cells (EC) are heterogeneous across and within tissues, reflecting distinct, specialised functions. EC heterogeneity has been proposed to underpin EC plasticity independently from vessel microenvironments. However, heterogeneity driven by contact-dependent or short-range cell-cell crosstalk cannot be evaluated with single cell transcriptomic approaches as spatial and contextual information is lost. Nonetheless, quantification of EC heterogeneity and understanding of its molecular drivers is key to developing novel therapeutics for cancer, cardiovascular diseases and for revascularisation in regenerative medicine.
Here, we developed an EC profiling tool (ECPT) to examine individual cells within intact monolayers. We used ECPT to characterise different phenotypes in arterial, venous and microvascular EC populations. In line with other studies, we measured heterogeneity in terms of cell cycle, proliferation, and junction organisation. ECPT uncovered a previously under-appreciated single-cell heterogeneity in NOTCH activation. We correlated cell proliferation with different NOTCH activation states at the single cell and population levels. The positional and relational information extracted with our novel approach is key to elucidating the molecular mechanisms underpinning EC heterogeneity.
... In fact, disruption of Notch signalling leads to loss of arterial markers and an adoption of venous identity (Gridley, 2010;Swift and Weinstein, 2009), suggesting that the Notch signalling pathway represses the venous identity. Additionally, the transmembrane protein ephrinB2 is specifically expressed in aECs and its receptor EphB4 in vECs (Torres-Vázquez et al., 2003;H. U. Wang et al., 1998). ...
... U. Wang et al., 1998). The mentioned Eph-Ephrin family members' expression are modulated by the Notch pathway (Torres-Vázquez et al., 2003). The nuclear receptor COUP-TFII actively represses Notch activity in vECs (Swift andWeinstein, 2009) (You et al., 2005), being one of the venous markers that contribute to venous identity. ...
Die innerste Schicht von Blutgefäßen wird durch Endothelzellen geformt. Dort haben sie das Potential neue Blutgefäße durch einen Prozess Namens Angiogenese zu bilden. In Krebspatienten wurde gezeigt, dass Medikamente, die auf Mikrotubuli zielen, die tumorassoziierte Angiogen ese hemmen. Diese Erkenntnis lässt auf eine Rolle der Mikrotubuli-Dynamik im Prozess der Angiogenese schließen. Die fein abgestimmte Mikrotubulus-Dynamik wird durch posttranslationale Tubulinmodifikationen, wie die durch die Vasohibin-1 katalysierte Mikrotubuli-Detyrosinierung, moduliert. Dennoch sind die Rollen der Mikrotubuli-Dynamik und -Detyrosinierung während der Angiogenese noch nicht verstanden. Ich konnte zeigen, dass Mikrotubuli in aussprossenden Zellen schneller und für kürzere Zeit wachsen, und dass sie in Abhängigkeit vom Blutfluss stabilisiert werden. Funktionelle Studien haben gezeigt, dass die Dynamik der Mikrotubuli eine Rolle bei der Streckung und Proliferation von Endothelzellen spielt und dadurch für die korrekte Gefäßmorphogenese notwendig ist. Vasohibin-1 detyrosiniert α-Tubulin und wird im Endothel von Zebrafischen stark exprimiert. Ich habe herausgefunden, dass endotheliales Tubulin vorwiegend in aus sprossenden Gefäßen der hinteren Kardinalvene detyrosiniert wird. Bei sekundären Aus sprossungen führte der Funktionsverlust von Vasohibin-1 zu einer allgemeinen Abnahme der Mikrotubuli-Detyrosinierung, was zu einem abnormalen Sprossungsverhalten führte. Es unter Verlust von Vasohibin-1 eine vermehrte Zellteilung und eine erhöhte Zellzahl in sekundären Aussprossungen gibt. Infolge dessen scheitern diese Zellen daran die Lymphgefäße zu bilden und bauen stattdessen überschüssige Verbindungen zwischen den Venen. Meine Erkenntnisse lassen vermuten, dass die Tubulin-Detyrosinierung spezifisch die Zellteilung in den sekundären Aussprossungen kontrolliert, um die Bildung der venösen und lymphatischen Gefäße im Zebrafisch-Schwanz zu erreichen.
... This includes change in cell polarity, migration, proliferation, apoptosis, differentiation, and variability in cell-to-cell contacts (Jakobsson et al., 2010;Geudens and Gerhardt, 2011). Further, ECs have a remarkable plasticity and exhibit heterogeneous morphological and molecular signatures to meet specific needs of the vessels and organs in which they reside (Torres-Vá zquez et al., 2003;Aird, 2012;Potente and Mäkinen, 2017). ...
Arteries and veins form in a stepwise process that combines vasculogenesis and sprouting angiogenesis. Despite extensive data on the mechanisms governing blood vessel assembly at the single-cell level, little is known about how collective cell migration contributes to the organization of the balanced distribution between arteries and veins. Here, we use an endothelial-specific zebrafish reporter, arteriobow, to label small cohorts of arterial cells and trace their progeny from early vasculogenesis throughout arteriovenous remodeling. We reveal that the genesis of arteries and veins relies on the coordination of 10 types of collective cell dynamics. Within these behavioral categories, we identify a heterogeneity of collective cell motion specific to either arterial or venous remodeling. Using pharmacological blockade, we further show that cell-intrinsic Notch signaling and cell-extrinsic blood flow act as regulators in maintaining the heterogeneity of collective endothelial cell behavior, which, in turn, instructs the future territory of arteriovenous remodeling.
... Instead of this negative role in the developmental angiogenesis, Notch signaling plays positive role in the LV-to-BV transdifferentiation and thereby promote the prompt formation of early-regenerated brain BVs. The membrane ligand/receptor Delta/Notch could paracellularly activate the downstream signaling between two neighboring endothelial cells (Villa et al., 2001;Torres-Vazquez et al., 2003). After injury, expressions of both the ligand Dll4 and the receptor Notch1a as well as the Notch functional reporter and downstream target gene in the stand-alone, transdifferentiating iLVs implicate that the activation of Notch . ...
Acute ischemic stroke damages regional brain blood vessel (BV) network. Urgent recovery of basic blood flows, which represents the earliest regenerated BVs, are critical to improve clinical outcomes and minimize lethality. Although the late-regenerated BVs have been implicated to form via growing along the meninge-derived lymphatic vessels (iLVs), mechanisms underlying the early, urgent BV regeneration remain elusive. Using zebrafish cerebrovascular injury models, we show that the earliest regenerated BVs come from lymphatic transdifferentiation, a hitherto unappreciated process in vertebrates. Mechanistically, LV-to-BV transdifferentiation occurs exclusively in the stand-alone iLVs through Notch activation. In the track iLVs adhered by nascent BVs, transdifferentiation never occurs because the BV-expressing EphrineB2a paracellularly activates the iLV-expressing EphB4a to inhibit Notch activation. Suppression of LV-to-BV transdifferentiation blocks early BV regeneration and becomes lethal. These results demonstrate that urgent BV regeneration occurs via lymphatic transdifferentiation, suggesting this process and key regulatory molecules EphrinB2a/EphB4a/Notch as new post-ischemic therapeutic targets.
... They hypothesized the target of miR-133 being pro-renin receptor (PRR), whose silencing decreased Ang II-induced apoptosis [39]. Since arterial and venous ECs have different embryonic origins and show distinct molecular and functional identities, it can be opportune to choose accurately the endothelial subtype to model a CVD [40]. For example, in 2005, Deng et al. investigated the molecular cause of the different susceptibility to atherosclerosis between arteries and veins, finding that the basal gene expression pattern of saphenous vein ECs exhibit a higher protection against endothelial dysfunctions compared to coronary artery ECs, hinting arterial cells as a better model to study atherosclerosis. ...
The availability of appropriate and reliable in vitro cell models recapitulating human cardiovascular diseases has been the aim of numerous researchers, in order to retrace pathologic phenotypes, elucidate molecular mechanisms, and discover therapies using simple and reproducible techniques. In the past years, several human cell types have been utilized for these goals, including heterologous systems, cardiovascular and non-cardiovascular primary cells, and embryonic stem cells. The introduction of induced pluripotent stem cells and their differentiation potential brought new prospects for large-scale cardiovascular experiments, bypassing ethical concerns of embryonic stem cells and providing an advanced tool for disease modeling, diagnosis, and therapy. Each model has its advantages and disadvantages in terms of accessibility, maintenance, throughput, physiological relevance, recapitulation of the disease. A higher level of complexity in diseases modeling has been achieved with multicellular co-cultures. Furthermore, the important progresses reached by bioengineering during the last years, together with the opportunities given by pluripotent stem cells, have allowed the generation of increasingly advanced in vitro three-dimensional tissue-like constructs mimicking in vivo physiology. This review provides an overview of the main cell models used in cardiovascular research, highlighting the pros and cons of each, and describing examples of practical applications in disease modeling.
... With regards to ephrin and Eph receptor expression in context of viral infection, the epithelium, endothelium and immune cells are of specific interest. Expression for these tissues is described in Table 1 [11,20,21]. ...
Ephrin-Eph signaling is a receptor tyrosine kinase signaling pathway involved in a variety of cellular mechanisms, of which many are related to the adhesion or migration of cells. Both the Eph receptor and ephrin ligand are abundantly present on a wide variety of cell types, and strongly evolutionary conserved. This review provides an overview of how 18 genetically diverse viruses utilize the Eph receptor (Eph), ephrin ligand (ephrin) or ephrin-Eph signaling to their advantage in their viral life cycle. Both Ephs and ephrins have been shown to serve as entry receptors for a variety of viruses, via both membrane fusion and endocytosis. Ephs and ephrins are also involved in viral transmission by vectors, associated with viral replication or persistence and lastly to neurological damage caused by viral infection. Although therapeutic opportunities targeting Ephs or ephrins do not seem feasible yet, the current research does propose two models for the viral usage of ephrin-Eph signaling. Firstly, the viral entry model, in which membrane molecules are used for viral entry, leading to cells being used for replication or as a transporter. Secondly, the advantageous expression ephrin-Eph signaling model, where viruses adapt the expression of Ephs or ephrins to change cell-cell interaction to their advantage. These models can guide future research questions on the usage of Ephs or ephrins by viruses and therapeutic opportunities.
