scholarly journals Modulation of cell signalling and sulfation in cardiovascular development and disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tiago Justo ◽  
Antonie Martiniuc ◽  
Gurtej K. Dhoot
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Cell Signalling ◽  
Right Atrial ◽  
Cardiovascular Development ◽  
Endothelial Lining ◽  
Dynamic Changes ◽  
Adult Cardiomyocytes ◽  
Cell Lining

AbstractSulf1/Sulf2 genes are highly expressed during early fetal cardiovascular development but down-regulated during later stages correlating with a number of cell signalling pathways in a positive or a negative manner. Immunocytochemical analysis confirmed SULF1/SULF2 expression not only in endothelial cell lining of blood vessels but also in the developing cardiomyocytes but not in the adult cardiomyocytes despite persisting at reduced levels in the adult endothelial cells. The levels of both SULFs in adult ischemic human hearts and in murine hearts following coronary occlusion increased in endothelial lining of some regional blood vessels but with little or no detection in the cardiomyocytes. Unlike the normal adult heart, the levels of SULF1 and SULF2 were markedly increased in the adult canine right-atrial haemangiosarcoma correlating with increased TGFβ cell signalling. Cell signalling relationship to ischaemia was further confirmed by in vitro hypoxia of HMec1 endothelial cells demonstrating dynamic changes in not only vegf and its receptors but also sulfotransferases and Sulf1 & Sulf2 levels. In vitro hypoxia of HMec1 cells also confirmed earlier up-regulation of TGFβ cell signalling revealed by Smad2, Smad3, ALK5 and TGFβ1 changes and later down-regulation correlating with Sulf1 but not Sulf2 highlighting Sulf1/Sulf2 differences in endothelial cells under hypoxia.

scholarly journals Phospholipase Cγ Activation Drives Increased Production of Autotaxin in Endothelial Cells and Lysophosphatidic Acid-Dependent Regression

2010 ◽  
Vol 30 (10) ◽  
pp. 2401-2410 ◽  
Author(s):  
Eunok Im ◽  
Ruta Motiejunaite ◽  
Jorge Aranda ◽  
Eun Young Park ◽  
Lorenzo Federico ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Lysophosphatidic Acid ◽  
Vascular Endothelial ◽  
Additional Mechanism ◽  
Phospholipase Cγ1 ◽  
Common Substrate ◽  
Phosphoinositide 3 Kinase ◽  
Endothelial Growth Factor

ABSTRACT We previously reported that vascular endothelial growth factor (VEGF)-dependent activation of phospholipase Cγ1 (PLCγ) regulated tube stability by competing with phosphoinositide 3-kinase (PI3K) for their common substrate. Here we describe an additional mechanism by which PLCγ promoted regression of tubes and blood vessels. Namely, it increased the level of autotaxin (ATX), which is a secreted form of lysophospholipase D that produces lysophosphatidic acid (LPA). LPA promoted motility of endothelial cells, leading to disorganization/regression of tubes in vitro. Furthermore, mice that under- or overexpressed members of this intrinsic destabilization pathway showed either delayed or accelerated, respectively, regression of blood vessels. We conclude that endothelial cells can be instructed to engage a PLCγ-dependent intrinsic destabilization pathway that results in the production of soluble regression factors such as ATX and LPA. These findings are likely to potentiate ongoing efforts to prevent, manage, and eradicate numerous angiogenesis-based diseases such as proliferative diabetic retinopathy and solid tumors.

scholarly journals Human iPSC-derived mesodermal progenitor cells preserve their vasculogenesis potential after extrusion and form hierarchically organized blood vessels

2021 ◽  
Author(s):  
Leyla Dogan ◽  
Ruben Scheuring ◽  
Nicole Wagner ◽  
Yuichiro Ueda ◽  
Philipp Woersdoerfer ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Progenitor Cells ◽  
Vessel Wall ◽  
De Novo ◽  
Hierarchical Organization ◽  
Wall Structure ◽  
Electron Microscopic ◽  
Vessel Formation

Post-fabrication formation of a proper vasculature remains an unresolved challenge in bioprinting. Established strategies focus on the supply of the fabricated structure with nutrients and oxygen and either rely on the mere formation of a channel system using fugitive inks, or additionally use mature endothelial cells and/or peri-endothelial cells such as smooth muscle cells for the formation of blood vessels in vitro. Functional vessels, however, exhibit a hierarchical organization and multilayered wall structure that is important for their function. Human induced pluripotent stem cell-derived mesodermal progenitor cells (hiMPCs) have been shown to possess the capacity to form blood vessels in vitro, but have so far not been assessed for their applicability in bioprinting processes. Here, we demonstrate that hiMPCs, after formulation into an alginate/collagen type 1 bioink and subsequent extrusion, retain their ability to give rise to the formation of complex vessels that display a hierarchical network in a process that mimicks the embryonic steps of vessel formation by vasculogenesis. Histological evaluations at different time points of extrusion revealed initial formation of spheres, followed by lumen formation and further structural maturation as evidenced by building a multilayered vessel wall and a vascular network. These findings are supported by immunostainings for endothelial and peri-endothelial cell markers as well as electron microscopic analyses at the ultrastructural level. Moreover, capillary-like vessel structures deposited a basement membrane-like matrix structure at the basal side between the vessel wall and the alginate-collagen matrix. These results evidence the applicability and great potential of hiMPCs for the bioprinting of vascular structures mimicking the basic morphogenetic steps of de novo vessel formation during embryogenesis.

scholarly journals Kisspeptin-10 Inhibits Angiogenesis in Human Placental Vessels ex Vivo and Endothelial Cells in Vitro

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5927-5934 ◽  
Author(s):  
Thayalini Ramaesh ◽  
James J. Logie ◽  
Antonia K. Roseweir ◽  
Robert P. Millar ◽  
Brian R. Walker ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Ex Vivo ◽  
Umbilical Vein ◽  
Biologically Active ◽  
Trophoblast Invasion ◽  
In Vitro Assays ◽  
Dependent Manner ◽  
Inhibition Of Proliferation

Recent studies suggest that kisspeptin (a neuropeptide central to the regulation of gonadotrophin secretion) has diverse roles in human physiology, including a putative role in implantation and placental function. Kisspeptin and its receptor are present in human blood vessels, where they mediate vasoconstriction, and kisspeptin is known to inhibit tumor metastasis and trophoblast invasion, both processes involving angiogenesis. We hypothesized that kisspeptin contributes to the regulation of angiogenesis in the reproductive system. The presence of the kisspeptin receptor was confirmed in human placental blood vessels and human umbilical vein endothelial cells (HUVEC) using immunochemistry. The ability of kisspeptin-10 (KP-10) (a shorter biologically active processed peptide) to inhibit angiogenesis was tested in explanted human placental arteries and HUVEC using complementary ex vivo and in vitro assays. KP-10 inhibited new vessel sprouting from placental arteries embedded in Matrigel and tube-like structure formation by HUVEC, in a concentration-dependent manner. KP-10 had no effect on HUVEC viability or apoptosis but induced concentration-dependent inhibition of proliferation and migration. In conclusion, KP-10 has antiangiogenic effects and, given its high expression in the placenta, may contribute to the regulation of angiogenesis in this tissue.

Abstract 34: Human Cardiac Mesenchymal Cell Derived Extracellular Vesicles Promote Angiogenesis Through Angiopoietin-TIE2 Signaling

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Asif Pathan ◽  
Talha Farid ◽  
Abdur Rahman Khan ◽  
Marjan Nasr ◽  
Marcin Wysoczynski ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Extracellular Vesicles ◽  
Embryonic Stem ◽  
Tube Formation ◽  
Right Atrial ◽  
Boyden Chamber ◽  
Human Umbilical Cord ◽  
Angiogenic Activity ◽  
Cell Based Therapy

Cell-based therapy is considered a promising approach to treat the damaged heart due to myocardial infarction. Although the mechanisms for their beneficial action are not yet clear, exosome/extracellular vesicles (EVs) secreted by these cells may be involved in their reparative paracrine signaling. Previous studies have suggested that EVs isolated from several cell types (e.g. cardiosphere-derived cells, embryonic stem cell, CD34+ stem cells) induce angiogenic activity both in vitro and in vivo . Here, we investigated whether EVs secreted by adult human cardiac mesenchymal cells (hCMCs) exhibit pro-angiogenic activity, and if so, what signaling molecules are involved in this process. hCMCs were isolated from right atrial appendage of patients undergoing cardiac procedures and were characterized by the expression of classical mesenchymal markers- CD29 (99.1%), CD73 (99.0%), CD90 (20.4%), CD105 (99.3%), CD 31 (16.8%), CD34 (0.9%) and CD45 (0.1%). EVs isolated from serum-free 24-hour hCMC conditioned media using PEG4000-based precipitation technique exhibited two distinct population of particles with size range of 10-60nm and 100-500nm in diameter; expressed characteristic exosomal markers- CD63, HSP70, Flotillin-1 and were negative for cellular organelle markers- calreticulin (ER and apoptotic bodies), prohibitin (mitochondria), GM130 (Golgi), Lamin B (nuclear protein), β-actin (cytoskeleton) and PMP70 (peroxisomes) as determined by immunoblotting. In vitro assays revealed that hCMC EVs promote human umbilical cord endothelial cells (HUVECs) proliferation, transwell migration in Boyden chamber and tube formation on Matrigel, indicative of enhanced angiogenesis. Angiogenic proteomic array identified that angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2) proteins are highly enriched in EVs secreted by hCMCs. Furthermore, hCMC EV mediated HUVEC migration and tube formation was inhibited by TIE2 kinase inhibitor. Overall, these findings suggest that ANG-1 and ANG-2 are the key component of hCMC secreted EVs and they promote angiogenesis by activating TIE2 receptor in endothelial cells.

scholarly journals Plasminogen activator inhibitor-1 secretion of endothelial cells increases fibrinolytic resistance of an in vitro fibrin clot: evidence for a key role of endothelial cells in thrombolytic resistance

Blood ◽  
1996 ◽  
Vol 87 (10) ◽  
pp. 4204-4213 ◽  
Author(s):  
S Handt ◽  
WG Jerome ◽  
L Tietze ◽  
RR Hantgan
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Time Dependent ◽  
Plasminogen Activator Inhibitor 1 ◽  
Necrosis Factor Alpha ◽  
Activator Inhibitor ◽  
Pai 1

Time-dependent thrombolytic resistance is a critical problem in thrombolytic therapy for acute myocardial infarction. Platelets have been regarded as the main source of plasminogen activator inhibitor-1 (PAI-1) found in occlusive platelet-rich clots. However, endothelial cells are also known to influence the fibrinolytic capacity of blood vessels, but their ability to actively mediate time-dependent thrombolytic resistance has not been fully established. We will show that, in vitro, tumor necrosis factor-alpha-stimulated endothelial cells secrete large amounts of PAI-1 over a period of hours, which then binds to fibrin and protects the clot from tissue plasminogen activator- induced fibrinolysis. In vivo, endothelial cells covering atherosclerotic plaques are influenced by cytokines synthesized by plaque cells. Therefore, we propose that continuous activation of endothelial cells in atherosclerotic blood vessels, followed by elevated PAI-1 secretion and storage of active PAI-1 in the fibrin matrix, leads to clot stabilization. This scenario makes endothelial cells a major factor in time-dependent thrombolytic resistance.

Akt-1 Regulates Angiogenesis in Skin.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 845-845
Author(s):  
Tatiana Byzova ◽  
Juhua Chen ◽  
Payaningal R. Somanath
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Blood Vessels ◽  
Cell Function ◽  
Active Form ◽  
Endothelial Cell Migration ◽  
Matrix Composition ◽  
Adhesive Properties ◽  
Endothelial Cell Function

Abstract The major mechanism to adapt to ischemic conditions is the development of neovascularization, i.e. angiogenesis, a process driven by members of VEGF family of growth factors. Phosphoinositide 3-kinase/Akt pathway is a critical component of the signaling network that regulates endothelial cell function related to angiogenesis. VEGF treatment of endothelial cells results in rapid phosphorylation of Akt. Our studies demonstrated that Akt kinase activity is necessary for VEGF-induced and integrin-mediated endothelial cell adhesion and migration. Moreover, cell transfection with a constitutive active form of Akt (myr-Akt) leads to increased function of integrin receptors. Using Akt-1 null mice we found that Akt-1 controls VEGF-induced and integrin-dependent endothelial cell responses in vitro. Impaired endothelial cell migration and adhesion to extracellular matrix and a reduced rate of cell proliferation were observed in Akt-1 (−/−) endothelial cells compared to WT. There are three Akt isoforms with different tissue distribution, however, it appears that Akt-1 is a predominant isoform in skin and in skin microvasculature. This observation prompted us to perform series of in vivo experiments designed to assess the angiogenic response in skin in the absence of Akt-1. Angiogenesis assay using matrigel plugs revealed that the weight and hemoglobin content of matrigel plugs is about two fold higher in Akt (−/−) mice compared to WT mice. Tumor angiogenesis also appears to be enhanced in Akt(−/−) mice, resulting in the significantly lower degree of tumor necrosis. Blood vessels in Akt (−/−) mice appear to be smaller in diameter and have reduced laminin content. Our analysis revealed significant changes in blood vessel wall matrix composition of Akt (−/−) mice as compared to WT animals. These changes resulted in increased vascular permeability in skin of Akt (−/−) mice. Akt-1 is known to target multiple cellular processes including adhesive properties, cell survival, transcription and translation. It appears that the phenotype of Akt-1 (−/−) mice depends on the equilibrium between pro-angiogenic and anti-angiogenic roles of Akt-1 and reveals a central role for Akt-1 in the regulation of matrix production and maturation of blood vessels.

scholarly journals The Pregnant Syrian Hamster as a Model to Study Intravascular Trophoblasts and Associated Maternal Blood Vessel Changes

1979 ◽  
Vol 16 (5) ◽  
pp. 556-566 ◽  
Author(s):  
J. D. Burek ◽  
B. Goldberg ◽  
G. Hutchins ◽  
J. D. Strandberg
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Succinic Dehydrogenase ◽  
Maternal Blood ◽  
Arterial System ◽  
Elastic Membrane ◽  
Nonspecific Esterase ◽  
Endothelial Lining ◽  
Glycerophosphate Dehydrogenase ◽  
Poorly Differentiated

In pregnant Syrian hamsters (Mesocricetus auratus) used as an animal model for studying the migration of fetal trophoblasts and the associated changes in maternal blood vessels, intravascular trophoblasts migrated well beyond the blood vessels of the uterus and into the vessels of the mesometrium. They migrated beyond the decidua of the uterus, into the lumina of maternal uterine and mesometrial arteries, but not into veins. The arterial changes, which were often segmental, resembled those seen in the decidua and consisted of a replacement of normal smooth muscle cells by poorly differentiated stromal cells. Ultrastructurally, the trophoblasts were either above or below maternal endothelial cells. They occurred also as single or multiple layers within the lumina of arteries that lacked an endothelial lining. Apparent penetration of the elastic membrane by the fetal trophoblasts brought them into close apposition to maternal cells in the arterial wall. Histochemical studies showed heightened metabolic activity of the intravascular trophoblasts as suggested by strong histochemical reactions to nonspecific esterase, succinic dehydrogenase and the glycerophosphate dehydrogenase reactions. Thus, these metabolically active fetal trophoblasts actively migrate into the maternal arterial system, resulting in loss of endothelial cells and changes in the wall of the maternal arteries similar to those in the decidua at the uteroplacental junction.

scholarly journals Rapid Cytopathic Effects of Clostridium perfringens Beta-Toxin on Porcine Endothelial Cells

2010 ◽  
Vol 78 (7) ◽  
pp. 2966-2973 ◽  
Author(s):  
Corinne Gurtner ◽  
Francesca Popescu ◽  
Marianne Wyder ◽  
Esther Sutter ◽  
Friederike Zeeh ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Clostridium Perfringens ◽  
Proximal Jejunum ◽  
Endothelial Lining ◽  
Aortic Endothelial Cells ◽  
Type C ◽  
Mucosal Necrosis ◽  
Beta Toxin ◽  
Immunohistochemical Studies

ABSTRACT Clostridium perfringens type C isolates cause fatal, segmental necro-hemorrhagic enteritis in animals and humans. Typically, acute intestinal lesions result from extensive mucosal necrosis and hemorrhage in the proximal jejunum. These lesions are frequently accompanied by microvascular thrombosis in affected intestinal segments. In previous studies we demonstrated that there is endothelial localization of C. perfringens type C β-toxin (CPB) in acute lesions of necrotizing enteritis. This led us to hypothesize that CPB contributes to vascular necrosis by directly damaging endothelial cells. By performing additional immunohistochemical studies using spontaneously diseased piglets, we confirmed that CPB binds to the endothelial lining of vessels showing early signs of thrombosis. To investigate whether CPB can disrupt the endothelium, we exposed primary porcine aortic endothelial cells to C. perfringens type C culture supernatants and recombinant CPB. Both treatments rapidly induced disruption of the actin cytoskeleton, cell border retraction, and cell shrinkage, leading to destruction of the endothelial monolayer in vitro. These effects were followed by cell death. Cytopathic and cytotoxic effects were inhibited by neutralization of CPB. Taken together, our results suggest that CPB-induced disruption of endothelial cells may contribute to the pathogenesis of C. perfringens type C enteritis.

scholarly journals Development and Application of Endothelial Cells Derived From Pluripotent Stem Cells in Microphysiological Systems Models

2021 ◽  
Vol 8 ◽  
Author(s):  
Crystal C. Kennedy ◽  
Erin E. Brown ◽  
Nadia O. Abutaleb ◽  
George A. Truskey
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Blood Vessels ◽  
Pluripotent Stem Cells ◽  
The Body ◽  
Organ Systems ◽  
Temporal Waveform ◽  
Induced Pluripotent

The vascular endothelium is present in all organs and blood vessels, facilitates the exchange of nutrients and waste throughout different organ systems in the body, and sets the tone for healthy vessel function. Mechanosensitive in nature, the endothelium responds to the magnitude and temporal waveform of shear stress in the vessels. Endothelial dysfunction can lead to atherosclerosis and other diseases. Modeling endothelial function and dysfunction in organ systems in vitro, such as the blood–brain barrier and tissue-engineered blood vessels, requires sourcing endothelial cells (ECs) for these biomedical engineering applications. It can be difficult to source primary, easily renewable ECs that possess the function or dysfunction in question. In contrast, human pluripotent stem cells (hPSCs) can be sourced from donors of interest and renewed almost indefinitely. In this review, we highlight how knowledge of vascular EC development in vivo is used to differentiate induced pluripotent stem cells (iPSC) into ECs. We then describe how iPSC-derived ECs are being used currently in in vitro models of organ function and disease and in vivo applications.

Reconstituting Angiogenesis in Vitro

2013 ◽  
Vol 6 (273) ◽  
pp. ec99-ec99 ◽  
Author(s):  
Nancy R. Gough
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Single Cells ◽  
Morphological Characteristics ◽  
Collective Cell Migration ◽  
Endothelial Lining ◽  
Impaired Wound Healing ◽  
Link Type ◽  
Impaired Angiogenesis

New blood vessels form from existing ones through a process called angiogenesis. Excessive or impaired angiogenesis contribute to various diseases, including cancer and diabetic retinopathy (excessive angiogenesis) or diabetic foot ulcers and impaired wound healing (impaired angiogenesis). Thus, drugs that can influence this morphogenetic process are clinically important; however, the currently available methods to assay the effects of such drugs are limited. Nguyen et al. developed a three-dimensional platform consisting of two cylindrical channels in a collagen matrix. Into one channel, endothelial cells were injected and formed a “parent” vessel through which medium was perfused; into the other channel, various pro- or anti-angiogenic cocktails were perfused, creating a gradient through the intervening matrix. Introduction individually of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), or monocyte chemotactic protein-1 (MCP-1) failed to stimulate invasion of endothelial cells into the matrix, but introduction of sphingosine 1-phosphate (S1P) or the phorbol ester PMA stimulated migration of single cells (S1P) or collective cell migration (PMA). Two different cocktails containing combinations of these factors stimulated angiogenic sprouting that ultimately resulted in an endothelial lining of the factor-delivery channel and microvessels connecting the two channels. The integrity of the connected vessels was confirmed by tracking beads introduced into the vessels. Analysis of the morphological characteristics of the newly sprouting vessels confirmed that they recapitulated in vivo events, such as the formation of filopodia-extending tip cells and polarized stalk cells. Although introduction of either a VEGF inhibitor or an inhibitor of the S1P receptor blocked angiogenesis, examination of the morphological characteristics revealed differential effects on sprouting that depended on the inhibitor and the growth factor cocktail into which the inhibitor was introduced. Thus, this system could be useful in exploring mechanisms that regulate various steps in the angiogenic process and in screening for factors or drugs that alter this complex process.D.-H. T. Nguyen, S. C. Stapleton, M. T. Yang, S. S. Cha, C. K. Choi, P. A. Galie, C. S. Chen, Biomimetic model to reconstitute angiogenic sprouting morphogenesis in vitro. Proc. Natl. Acad. Sci. U.S.A.110, 6712–6717 (2013). [Abstract][Full Text]

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