scholarly journals Transcription Factor Control of Lymphatic Quiescence and Maturation of Lymphatic Neovessels in Development and Physiology

2021 ◽  
Vol 12 ◽  
Author(s):  
Zarah B. Tabrizi ◽  
Nada S. Ahmed ◽  
Joseph L. Horder ◽  
Sarah J. Storr ◽  
Andrew V. Benest
Keyword(s):  
Transcription Factor ◽  
Lymphatic System ◽  
Normal Development ◽  
Vascular System ◽  
Cellular Responses ◽  
Phenotypic Switching ◽  
Molecular Heterogeneity ◽  
Lymphatic Endothelial Cells ◽  
Pathological Conditions ◽  
Differential Transcription

The lymphatic system is a vascular system comprising modified lymphatic endothelial cells, lymph nodes and other lymphoid organs. The system has diverse, but critical functions in both physiology and pathology, and forms an interface between the blood vascular and immune system. It is increasingly evident that remodelling of the lymphatic system occurs alongside remodelling of the blood microvascular system, which is now considered a hallmark of most pathological conditions as well as being critical for normal development. Much attention has focussed on how the blood endothelium undergoes phenotypic switching in development and disease, resulting in over two decades of research to probe the mechanisms underlying the resulting heterogeneity. The lymphatic system has received less attention, and consequently there are fewer descriptions of functional and molecular heterogeneity, but differential transcription factor activity is likely an important control mechanism. Here we introduce and discuss significant transcription factors of relevance to coordinating cellular responses during lymphatic remodelling as the lymphatic endothelium dynamically changes from quiescence to actively remodelling.

scholarly journals The caudal heart of the eel a lymphatic heart.—Effect of the force with which the lymph- stream is propelled therefrom on the flow of blood in the vein into which the heart opens. — Explanation of the appearance of blood propelled in successive drops, as if from the heart, along the caudal vein.— Influence which the force of the lymph-stream from the heart exerts in accelerating and promoting the flow of blood in the caudal vein

1868 ◽  
Vol 16 ◽  
pp. 230-231
Keyword(s):  
Lymphatic System ◽  
Vascular System ◽  
True Nature ◽  
Rapid Succession ◽  
Caudal Vein ◽  
Lymphatic Heart ◽  
As If

To explain the true nature of the phenomenon of drops of blood propelled in rapid succession, as if from the caudal heart, along the caudal vein,—to prove thereby that the caudal heart belongs, not to the blood-vascular system, but to the lymphatic system,—and to inquire into the influence which the force of the lymph-stream from the caudal heart exerts in accelerating and promoting the flow of blood in the caudal vein, constitute the object of this paper. The great caudal vein of the eel is formed by the junction of two trunks, a larger and a smaller. It is into the smaller trunk, near its junction with the larger, that the caudal heart opens. At the opening, there is a valve which prevents regurgitation of the lymph back from the vein into the heart.

Lymphangiogenesis in development and disease

2007 ◽  
Vol 98 (08) ◽  
pp. 304-310 ◽  
Author(s):  
Ruediger Liersch ◽  
Michael Detmar
Keyword(s):  
Lymph Nodes ◽  
Cancer Metastasis ◽  
Lymphatic System ◽  
Vascular System ◽  
Malignant Tumors ◽  
Inflammatory Diseases ◽  
Transplant Rejection ◽  
Lymphatic Vessels ◽  
Lipid Uptake ◽  
Molecular Control

SummaryThe lymphatic vascular system plays an important role in the maintenance of fluid homeostasis, in the afferent immune response, in the intestinal lipid uptake and in the metastatic spread of malignant cells. The recent discovery of specific markers and growth factors for lymphatic endothelium and the establishment of genetic mouse models with impairment of lymphatic function have provided novel insights into the molecular control of the lymphatic system in physiology and in embryonic development. They have also identified molecular pathways whose mutational inactivation leads to human diseases associated with lymphedema. Moreover, the lymphatic system plays a major role in chronic inflammatory diseases and in transplant rejection. Importantly, malignant tumors can directly promote lymphangiogenesis within the primary tumor and in draining lymph nodes, leading to enhanced cancer metastasis to lymph nodes and beyond. Based upon these findings, novel therapeutic strategies are currently being developed that aim at inhibiting or promoting the formation and function of lymphatic vessels in disease.

scholarly journals Role of NFAT in the Progression of Diabetic Atherosclerosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Yaoyao Cai ◽  
Haipeng Yao ◽  
Zhen Sun ◽  
Ying Wang ◽  
Yunyun Zhao ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cardiovascular System ◽  
Signaling Pathways ◽  
Immune Cells ◽  
Target Genes ◽  
Vascular System ◽  
Foam Cell ◽  
Vascular Diseases ◽  
Regulatory Function ◽  
Foam Cell Formation

Nuclear factor of activated T cells (NFAT) is a transcription factor with a multidirectional regulatory function, that is widely expressed in immune cells, including cells in the cardiovascular system, and non-immune cells. A large number of studies have confirmed that calcineurin/NFAT signal transduction is very important in the development of vascular system and cardiovascular system during embryonic development, and plays some role in the occurrence of vascular diseases such as atherosclerosis, vascular calcification, and hypertension. Recent in vitro and in vivo studies have shown that NFAT proteins and their activation in the nucleus and binding to DNA-related sites can easily ɨnduce the expression of downstream target genes that participate in the proliferation, migration, angiogenesis, and vascular inflammation of vascular wall related cells in various pathophysiological states. NFAT expression is regulated by various signaling pathways, including CD137-CD137L, and OX40-OX40L pathways. As a functionally diverse transcription factor, NFAT interacts with a large number of signaling molecules to modulate intracellular and extracellular signaling pathways. These NFAT-centered signaling pathways play important regulatory roles in the progression of atherosclerosis, such as in vascular smooth muscle cell phenotypic transition and migration, endothelial cell injury, macrophage-derived foam cell formation, and plaque calcification. NFAT and related signaling pathways provide new therapeutic targets for vascular diseases such as atherosclerosis. Hence, further studies of the mechanism of NFAT in the occurrence and evolution of atherosclerosis remain crucial.

scholarly journals Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Michael RM Harrison ◽  
Xidi Feng ◽  
Guqin Mo ◽  
Antonio Aguayo ◽  
Jessi Villafuerte ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Lymphatic System ◽  
Vascular System ◽  
Heart Function ◽  
Lymphatic Vessels ◽  
Adult Zebrafish ◽  
Heart Patients ◽  
Scar Size ◽  
Lymphatic Vasculature ◽  
Zebrafish Heart

The cardiac lymphatic vascular system and its potentially critical functions in heart patients have been largely underappreciated, in part due to a lack of experimentally accessible systems. We here demonstrate that cardiac lymphatic vessels develop in young adult zebrafish, using coronary arteries to guide their expansion down the ventricle. Mechanistically, we show that in cxcr4a mutants with defective coronary artery development, cardiac lymphatic vessels fail to expand onto the ventricle. In regenerating adult zebrafish hearts the lymphatic vasculature undergoes extensive lymphangiogenesis in response to a cryoinjury. A significant defect in reducing the scar size after cryoinjury is observed in zebrafish with impaired Vegfc/Vegfr3 signaling that fail to develop intact cardiac lymphatic vessels. These results suggest that the cardiac lymphatic system can influence the regenerative potential of the myocardium.

ANGIOMATOSIS (HAMARTOMATOUS HEM-LYMPHANGIOMATOSIS)

PEDIATRICS ◽  
1961 ◽  
Vol 28 (1) ◽  
pp. 65-76
Author(s):  
Peter J. Koblenzer ◽  
Martin J. Bukowski
Keyword(s):  
Blood Vessels ◽  
Lymphatic System ◽  
Vascular System ◽  
Clinical Manifestations ◽  
Body Cavity ◽  
Histologic Examination ◽  
Peripheral Vascular ◽  
Osteolytic Lesions ◽  
System A

A case is described of a diffuse, possibly generalized, abnormality of a hamartomatous nature of the peripheral vascular system. A number of cases from the literature, which also appear to belong in this category, are summarized. Histologic examination shows that lymph and blood vessels may both be involved, though this may be essentially an abnormality of the lymphatic system in which extensive venolymphatic communications occur. The clinical manifestations vary according to the site of involvement and the extent of dissemination and also according to whether the lesions are predominantly hemangiomatous or lymphangiomatous. The main features are osteolytic lesions, visceromegaly, cutaneous hemangiomas or lymphangiomas and massive effusions into any body cavity. The effusions are usually chylous, sanguineous or a mixture of both. Any or all of these features may be present in any one case. The disease frequently has its onset in childhood or adolescence and tends to be progressive. If the lesions are widely disseminated or an effusion into a body cavity is present the outlook is grave. Treatment so far has been unsuccessful. Surgery may occasionally have a place. The term angiomatosis is employed to denote this condition not only to underline its potentially extensive nature but also to avoid debate as to whether it is essentially hemangiomatosis or lymphangiomatosis.

Retinoic acid establishes ventral retinal characteristics

Development ◽  
1996 ◽  
Vol 122 (1) ◽  
pp. 195-204 ◽  
Author(s):  
G.A. Hyatt ◽  
E.A. Schmitt ◽  
N. Marsh-Armstrong ◽  
P. McCaffery ◽  
U.C. Drager ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Retinoic Acid ◽  
Optic Nerve ◽  
Normal Development ◽  
Cell Content ◽  
Optic Stalk ◽  
Eye Field ◽  
Dorsal Retina ◽  
Choroid Fissure

The developing eye is known to be rich in retinoic acid (RA), and perturbations in RA levels during formation of the optic primordia, as well as RA receptor mutations, cause retinal malformations, especially in ventral eye regions. To test the hypothesis that RA plays a role in the establishment of ventral retinal characteristics, we examined several dorsal and ventral ocular markers in RA-treated zebrafish. The optic stalk represents the ventral-most region of the early eye field. During normal development, the optic stalks constrict, decreasing in width and are gradually replaced by the optic nerve. Systemic high RA levels cause an expansion in the optic stalk with an increased cell content and a patent lumen. In addition, the stalks do not constrict and persist into later stages of development indicating an enhancement of early ventral eye characteristics. Expression of the transcription factor pax[b], normally confined to the ventral retina, expands into the dorsal retina following RA treatment, whereas msh[c], normally expressed in the dorsal retinal pole, disappears. Activity of an aldehyde dehydrogenase that normally occupies the dorsal third of the retina is reduced or abolished following high systemic RA. When a localized RA source, an RA-soaked bead, is placed next to the developing eye, a fissure resembling the choroid fissure appears in the eye facing the bead. Taken together, these observations suggest that RA is involved in the determination of the ventral retina.

scholarly journals Unification of Opposites between Two Antioxidant Transcription Factors Nrf1 and Nrf2 in Mediating Distinct Cellular Responses to the Endoplasmic Reticulum Stressor Tunicamycin

Antioxidants ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 4 ◽  
Author(s):  
Yu-ping Zhu ◽  
Ze Zheng ◽  
Shaofan Hu ◽  
Xufang Ru ◽  
Zhuo Fan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Er Stress ◽  
Target Genes ◽  
Cellular Responses ◽  
Water Soluble ◽  
Heme Oxygenase 1 ◽  
Nuclear Factor ◽  
Activating Transcription Factor

The water-soluble Nrf2 (nuclear factor, erythroid 2-like 2, also called Nfe2l2) is accepted as a master regulator of antioxidant responses to cellular stress, and it was also identified as a direct target of the endoplasmic reticulum (ER)-anchored PERK (protein kinase RNA-like endoplasmic reticulum kinase). However, the membrane-bound Nrf1 (nuclear factor, erythroid 2-like 1, also called Nfe2l1) response to ER stress remains elusive. Herein, we report a unity of opposites between these two antioxidant transcription factors, Nrf1 and Nrf2, in coordinating distinct cellular responses to the ER stressor tunicamycin (TU). The TU-inducible transcription of Nrf1 and Nrf2, as well as GCLM (glutamate cysteine ligase modifier subunit) and HO-1 (heme oxygenase 1), was accompanied by activation of ER stress signaling networks. Notably, the unfolded protein response (UPR) mediated by ATF6 (activating transcription factor 6), IRE1 (inositol requiring enzyme 1) and PERK was significantly suppressed by Nrf1α-specific knockout, but hyper-expression of Nrf2 and its target genes GCLM and HO-1 has retained in Nrf1α−/− cells. By contrast, Nrf2−/−ΔTA cells with genomic deletion of its transactivation (TA) domain resulted in significant decreases of GCLM, HO-1 and Nrf1; this was accompanied by partial decreases of IRE1 and ATF6, rather than PERK, but with an increase of ATF4 (activating transcription factor 4). Interestingly, Nrf1 glycosylation and its trans-activity to mediate the transcriptional expression of the 26S proteasomal subunits, were repressed by TU. This inhibitory effect was enhanced by Nrf1α−/− and Nrf2−/−ΔTA, but not by a constitutive activator caNrf2ΔN (that increased abundances of the non-glycosylated and processed Nrf1). Furthermore, caNrf2ΔN also enhanced induction of PERK and IRE1 by TU, but reduced expression of ATF4 and HO-1. Thus, it is inferred that such distinct roles of Nrf1 and Nrf2 are unified to maintain cell homeostasis by a series of coordinated ER-to-nuclear signaling responses to TU. Nrf1α (i.e., a full-length form) acts in a cell-autonomous manner to determine the transcription of most of UPR-target genes, albeit Nrf2 is also partially involved in this process. Consistently, transactivation of ARE (antioxidant response element)-driven BIP (binding immunoglobulin protein)-, PERK- and XBP1 (X-box binding protein 1)-Luc reporter genes was mediated directly by Nrf1 and/or Nrf2. Interestingly, Nrf1α is more potent than Nrf2 at mediating the cytoprotective responses against the cytotoxicity of TU alone or plus tBHQ (tert-butylhydroquinone). This is also further supported by the evidence that the intracellular reactive oxygen species (ROS) levels are increased in Nrf1α−/− cells, but rather are, to our surprise, decreased in Nrf2−/−ΔTA cells.

scholarly journals Cholesterol-Induced Phenotypic Modulation of Smooth Muscle Cells to Macrophage/Fibroblast–like Cells Is Driven by an Unfolded Protein Response

2020 ◽  
Author(s):  
Abhijnan Chattopadhyay ◽  
Callie S. Kwartler ◽  
Kaveeta Kaw ◽  
Yanming Li ◽  
Anita Kaw ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Atherosclerotic Plaque ◽  
Plaque Formation ◽  
Phenotypic Switching ◽  
Unfolded Protein ◽  
Atherosclerotic Plaque Formation ◽  
Protein Response

Objective: Vascular smooth muscle cells (SMCs) dedifferentiate and initiate expression of macrophage markers with cholesterol exposure. This phenotypic switching is dependent on the transcription factor Klf4 (Krüppel-like factor 4). We investigated the molecular pathway by which cholesterol induces SMC phenotypic switching. Approach and Results: With exposure to free methyl-β-cyclodextrin cholesterol, SMCs decrease expression of contractile markers, activate Klf4, and upregulate a subset of macrophage and fibroblast markers characteristic of modulated SMCs that appear with atherosclerotic plaque formation. These phenotypic changes are associated with activation of all 3 pathways of the endoplasmic reticulum unfolded protein response (UPR), Perk (protein kinase RNA-like endoplasmic reticulum kinase), Ire (inositol-requiring enzyme) 1α, and Atf (activating transcription factor) 6. Blocking the movement of cholesterol from the plasma membrane to the endoplasmic reticulum prevents methyl-β-cyclodextrin cholesterol–induced UPR, Klf4 activation, and upregulation of the majority of macrophage and fibroblast markers. Cholesterol-induced phenotypic switching is also prevented by global UPR inhibition or specific inhibition of Perk signaling. Exposure to chemical UPR inducers, tunicamycin, and thapsigargin is sufficient to induce these same phenotypic transitions. Finally, analysis of published single-cell RNA sequencing data during atherosclerotic plaque formation in hyperlipidemic mice provides preliminary in vivo evidence of a role of UPR activation in modulated SMCs. Conclusions: Our data demonstrate that UPR is necessary and sufficient to drive phenotypic switching of SMCs to cells that resemble modulated SMCs found in atherosclerotic plaques. Preventing a UPR in hyperlipidemic mice diminishes atherosclerotic burden, and our data suggest that preventing SMC transition to dedifferentiated cells expressing macrophage and fibroblast markers contributes to this decreased plaque burden.

scholarly journals Dynamic Competition of Polycomb and Trithorax in Transcriptional Programming

2020 ◽  
Vol 89 (1) ◽  
pp. 235-253 ◽  
Author(s):  
Mitzi I. Kuroda ◽  
Hyuckjoon Kang ◽  
Sandip De ◽  
Judith A. Kassis
Keyword(s):  
Transcription Factor ◽  
Histone Modifications ◽  
Dna Sequences ◽  
Normal Development ◽  
Polycomb Group ◽  
Cell Type ◽  
Trithorax Group ◽  
Cell Type Specific ◽  
Chromatin Proteins ◽  
Regulatory Potential

Predicting regulatory potential from primary DNA sequences or transcription factor binding patterns is not possible. However, the annotation of the genome by chromatin proteins, histone modifications, and differential compaction is largely sufficient to reveal the locations of genes and their differential activity states. The Polycomb Group (PcG) and Trithorax Group (TrxG) proteins are the central players in this cell type–specific chromatin organization. PcG function was originally viewed as being solely repressive and irreversible, as observed at the homeotic loci in flies and mammals. However, it is now clear that modular and reversible PcG function is essential at most developmental genes. Focusing mainly on recent advances, we review evidence for how PcG and TrxG patterns change dynamically during cell type transitions. The ability to implement cell type–specific transcriptional programming with exquisite fidelity is essential for normal development.

scholarly journals NANOG expression in human development and cancerogenesis

2020 ◽  
Vol 245 (5) ◽  
pp. 456-464 ◽  
Author(s):  
Gašper Grubelnik ◽  
Emanuela Boštjančič ◽  
Ana Pavlič ◽  
Marina Kos ◽  
Nina Zidar
Keyword(s):  
Transcription Factor ◽  
Stem Cell ◽  
Human Development ◽  
Target Genes ◽  
Normal Development ◽  
Current Knowledge ◽  
Precancerous Lesions ◽  
Embryonic Stem ◽  
Predictive Marker ◽  
Nanog Expression

NANOG is an important stem cell transcription factor involved in human development and cancerogenesis. Its expression is complex and regulated on different levels. Moreover, NANOG protein might regulate hundreds of target genes at the same time. NANOG is crucial for preimplantation development phase and progressively decreases during embryonic stem cells differentiation, thus regulating embryonic and fetal development. Postnatally, NANOG is undetectable or expressed in very low amounts in the majority of human tissues. NANOG re-expression can be detected during cancerogenesis, already in precancerous lesions, with increasing levels of NANOG in high grade dysplasia. NANOG is believed to enable cancer cells to obtain stem-cell like properties, which are believed to be the source of expanding growth, tumor maintenance, metastasis formation, and tumor relapse. High NANOG expression in cancer is frequently associated with advanced stage, poor differentiation, worse overall survival, and resistance to treatment, and is therefore a promising prognostic and predictive marker. We summarize the current knowledge on the role of NANOG in cancerogenesis and development, including our own experience. We provide a critical overview of NANOG as a prognostic and diagnostic factor, including problems regarding its regulation and detection. Impact statement NANOG has emerged as a key stem cell transcription factor in normal development and cancerogenesis. It is generally regarded as a good prognostic and predictive factor in various human cancers. It is less known that it is expressed already at precancerous stages in various organs, suggesting that finally an ideal candidate diagnostic marker has been discovered, enabling to distinguish between true dysplasia and reactive atypia. NANOG regulation is complex, and new insights into our understanding of its regulation might provide important information for future development in a broad field of two entirely different processes, i.e. normal development and cancerogenesis, showing how a physiologic mechanism can be used and abused, transforming itself into a key mechanism of disease development and progression.

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