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Open accessJournal ArticleDOI: 10.3389/FPHYS.2020.623769

Endothelial Cell Orientation and Polarity Are Controlled by Shear Stress and VEGF Through Distinct Signaling Pathways.

02 Mar 2021-Frontiers in Physiology (Frontiers Media SA)-Vol. 11, pp 623769-623769
Abstract: Vascular networks form, remodel and mature under the influence of multiple signals of mechanical or chemical nature. How endothelial cells read and interpret these signals, and how they integrate information when they are exposed to both simultaneously is poorly understood. Here, we show using flow-induced shear stress and VEGF-A treatment on endothelial cells in vitro, that the response to the magnitude of a mechanical stimulus is influenced by the concentration of a chemical stimulus, and vice versa. By combining different flow levels and different VEGF-A concentrations, front-rear polarity of endothelial cells against the flow direction was established in a flow and VEGF-A dose-response while their alignment with the flow displayed a biphasic response depending on the VEGF-A dose (perpendicular at physiological dose, aligned at no or pathological dose of VEGF-A). The effect of pharmaceutical inhibitors demonstrated that while VEGFR2 is essential for both polarity and orientation establishment in response to flow with and without VEGF-A, different downstream effectors were engaged depending on the presence of VEGF-A. Thus, Src family inhibition (c-Src, Yes, Fyn together) impaired alignment and polarity without VEGF-A while FAK inhibition modified polarity and alignment only when endothelial cells were exposed to VEGF-A. Studying endothelial cells in the aortas of VEGFR2Y949F mutant mice and SRC iEC-KO mice confirmed the role of VEGFR2 and specified the role of c-SRC in vivo. Endothelial cells of VEGFR2Y949F mutant mice lost their polarity and alignment while endothelial cells from SRC iEC-KO mice only showed reduced polarity. We propose here that VEGFR2 is a sensor able to integrate chemical and mechanical information simultaneously and that the underlying pathways and mechanisms activated will depend on the co-stimulation. Flow alone shifts VEGFR2 signaling toward a Src family pathway activation and a junctional effect (both in vitro and in vivo) while flow and VEGF-A together shift VEGFR2 signaling toward focal adhesion activation (in vitro) both modifying cell responses that govern orientation and polarity.

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Topics: Endothelial stem cell (55%), Polarity (physics) (54%), Focal adhesion (51%) ... read more
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7 results found


Open accessJournal ArticleDOI: 10.3390/IJMS222111545
Abstract: Atherosclerosis is one of the most important problems in modern medicine. Its high prevalence and social significance determine the need for a better understanding of the mechanisms of the disease’s development and progression. Lipid metabolism and its disorders are one of the key links in the pathogenesis of atherosclerosis. Lipids are involved in many processes, including those related to the mechanoreception of endothelial cells. The multifaceted role of lipids in endothelial mechanobiology and mechanisms of atherogenesis are discussed in this review. Endothelium is involved in ensuring adequate vascular hemodynamics, and changes in blood flow characteristics are detected by endothelial cells and affect their structure and function.

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Topics: Endothelium (53%), Mechanobiology (53%), Lipid metabolism (53%) ... read more

1 Citations


Open accessJournal ArticleDOI: 10.1002/ADMA.202102661
Ariel A. Szklanny1, Majd Machour1, Idan Redenski1, Václav Chochola2  +10 moreInstitutions (3)
01 Oct 2021-Advanced Materials
Abstract: Engineering hierarchical vasculatures is critical for creating implantable functional thick tissues. Current approaches focus on fabricating mesoscale vessels for implantation or hierarchical microvascular in vitro models, but a combined approach is yet to be achieved to create engineered tissue flaps. Here, millimetric vessel-like scaffolds and 3D bioprinted vascularized tissues interconnect, creating fully engineered hierarchical vascular constructs for implantation. Endothelial and support cells spontaneously form microvascular networks in bioprinted tissues using a human collagen bioink. Sacrificial molds are used to create polymeric vessel-like scaffolds and endothelial cells seeded in their lumen form native-like endothelia. Assembling endothelialized scaffolds within vascularizing hydrogels incites the bioprinted vasculature and endothelium to cooperatively create vessels, enabling tissue perfusion through the scaffold lumen. Using a cuffing microsurgery approach, the engineered tissue is directly anastomosed with a rat femoral artery, promoting a rich host vasculature within the implanted tissue. After two weeks in vivo, contrast microcomputer tomography imaging and lectin perfusion of explanted engineered tissues verify the host ingrowth vasculature's functionality. Furthermore, the hierarchical vessel network (VesselNet) supports in vitro functionality of cardiomyocytes. Finally, the proposed approach is expanded to mimic complex structures with native-like millimetric vessels. This work presents a novel strategy aiming to create fully-engineered patient-specific thick tissue flaps.

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Topics: 3D bioprinting (54%), Tissue engineering (50%)

1 Citations


Open accessJournal ArticleDOI: 10.1186/S12885-021-08431-1
Chao Chen1, Yan Qun Liu1, Shi Xiang Qiu1, Ya Li1  +3 moreInstitutions (1)
11 Jun 2021-BMC Cancer
Abstract: BACKGROUNDS Liver hepatocellular carcinoma (HCC) is one of the most malignant tumors, of which prognosis is unsatisfactory in most cases and metastatic of HCC often results in poor prognosis. In this study, we aimed to construct a metastasis- related mRNAs prognostic model to increase the accuracy of prediction of HCC prognosis. METHODS Three hundred seventy-four HCC samples and 50 normal samples were downloaded from The Cancer Genome Atlas (TCGA) database, involving transcriptomic and clinical data. Metastatic-related genes were acquired from HCMBD website at the same time. Two hundred thirty-three samples were randomly divided into train dataset and test dataset with a proportion of 1:1 by using caret package in R. Kaplan-Meier method and univariate Cox regression analysis and lasso regression analysis were performed to obtain metastasis-related mRNAs which played significant roles in prognosis. Then, using multivariate Cox regression analysis, a prognostic prediction model was established. Transcriptome and clinical data were combined to construct a prognostic model and a nomogram for OS evaluation. Functional enrichment in high- and low-risk groups were also analyzed by GSEA. An entire set based on The International Cancer Genome Consortium(ICGC) database was also applied to verify the model. The expression levels of SLC2A1, CDCA8, ATG10 and HOXD9 are higher in tumor samples and lower in normal tissue samples. The expression of TPM1 in clinical sample tissues is just the opposite. RESULTS One thousand eight hundred ninety-five metastasis-related mRNAs were screened and 6 mRNAs were associated with prognosis. The overall survival (OS)-related prognostic model based on 5 MRGs (TPM1,SLC2A1, CDCA8, ATG10 and HOXD9) was significantly stratified HCC patients into high- and low-risk groups. The AUC values of the 5-gene prognostic signature at 1 year, 2 years, and 3 years were 0.786,0.786 and 0.777. A risk score based on the signature was a significantly independent prognostic factor (HR = 1.434; 95%CI = 1.275-1.612; P < 0.001) for HCC patients. A nomogram which incorporated the 5-gene signature and clinical features was also built for prognostic prediction. GSEA results that low- and high-risk group had an obviously difference in part of pathways. The value of this model was validated in test dataset and ICGC database. CONCLUSION Metastasis-related mRNAs prognostic model was verified that it had a predictable value on the prognosis of HCC, which could be helpful for gene targeted therapy.

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Open accessJournal ArticleDOI: 10.3390/JCDD8080090
Laura A. Dyer1, Sandra Rugonyi2Institutions (2)
Abstract: In congenital heart disease, the presence of structural defects affects blood flow in the heart and circulation. However, because the fetal circulation bypasses the lungs, fetuses with cyanotic heart defects can survive in utero but need prompt intervention to survive after birth. Tetralogy of Fallot and persistent truncus arteriosus are two of the most significant conotruncal heart defects. In both defects, blood access to the lungs is restricted or non-existent, and babies with these critical conditions need intervention right after birth. While there are known genetic mutations that lead to these critical heart defects, early perturbations in blood flow can independently lead to critical heart defects. In this paper, we start by comparing the fetal circulation with the neonatal and adult circulation, and reviewing how altered fetal blood flow can be used as a diagnostic tool to plan interventions. We then look at known factors that lead to tetralogy of Fallot and persistent truncus arteriosus: namely early perturbations in blood flow and mutations within VEGF-related pathways. The interplay between physical and genetic factors means that any one alteration can cause significant disruptions during development and underscore our need to better understand the effects of both blood flow and flow-responsive genes.

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Topics: Persistent truncus arteriosus (61%), Tetralogy of Fallot (56%), Fetal circulation (56%) ... read more

Journal ArticleDOI: 10.1002/ADHM.202101186
Yuji Nashimoto1, Minori Abe1, Ryota Fujii1, Noriko Taira1  +6 moreInstitutions (3)
Abstract: Microphysiological systems (MPS) or organs-on-chips (OoC) can emulate the physiological functions of organs in vitro and are effective tools for determining human drug responses in preclinical studies. However, the analysis of MPS has relied heavily on optical tools, resulting in difficulties in real-time and high spatial resolution imaging of the target cell functions. In this study, the role of scanning probe microscopy (SPM) as an analytical tool for MPS is evaluated. An access hole is made in a typical MPS system with stacked microchannels to insert SPM probes into the system. For the first study, a simple vascular model composed of only endothelial cells is prepared for SPM analysis. Changes in permeability and local chemical flux are quantitatively evaluated during the construction of the vascular system. The morphological changes in the endothelial cells after flow stimulation are imaged at the single-cell level for topographical analysis. Finally, the possibility of adapting the permeability and topographical analysis using SPM for the intestinal vascular system is further evaluated. It is believed that this study will pave the way for an in situ permeability assay and structural analysis of MPS using SPM.

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53 results found


Open accessJournal ArticleDOI: 10.1016/J.CELL.2011.08.039
16 Sep 2011-Cell
Abstract: Blood vessels form extensive networks that nurture all tissues in the body. Abnormal vessel growth and function are hallmarks of cancer and ischemic and inflammatory diseases, and they contribute to disease progression. Therapeutic approaches to block vascular supply have reached the clinic, but limited efficacy and resistance pose unresolved challenges. Recent insights establish how endothelial cells communicate with each other and with their environment to form a branched vascular network. The emerging principles of vascular growth provide exciting new perspectives, the translation of which might overcome the current limitations of pro- and antiangiogenic medicine.

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Topics: Sprouting angiogenesis (58%), Angiogenesis (51%)

1,924 Citations


Open accessJournal ArticleDOI: 10.1152/PHYSREV.00047.2009
Jeng Jiann Chiu1, Shu ChienInstitutions (1)
Abstract: Vascular endothelial cells (ECs) are exposed to hemodynamic forces, which modulate EC functions and vascular biology/pathobiology in health and disease. The flow patterns and hemodynamic forces are not uniform in the vascular system. In straight parts of the arterial tree, blood flow is generally laminar and wall shear stress is high and directed; in branches and curvatures, blood flow is disturbed with nonuniform and irregular distribution of low wall shear stress. Sustained laminar flow with high shear stress upregulates expressions of EC genes and proteins that are protective against atherosclerosis, whereas disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote atherogenesis. These findings have led to the concept that the disturbed flow pattern in branch points and curvatures causes the preferential localization of atherosclerotic lesions. Disturbed flow also results in postsurgical neointimal hyperplasia and contributes to pathophysiology of clinical conditions such as in-stent restenosis, vein bypass graft failure, and transplant vasculopathy, as well as aortic valve calcification. In the venous system, disturbed flow resulting from reflux, outflow obstruction, and/or stasis leads to venous inflammation and thrombosis, and hence the development of chronic venous diseases. Understanding of the effects of disturbed flow on ECs can provide mechanistic insights into the role of complex flow patterns in pathogenesis of vascular diseases and can help to elucidate the phenotypic and functional differences between quiescent (nonatherogenic/nonthrombogenic) and activated (atherogenic/thrombogenic) ECs. This review summarizes the current knowledge on the role of disturbed flow in EC physiology and pathophysiology, as well as its clinical implications. Such information can contribute to our understanding of the etiology of lesion development in vascular niches with disturbed flow and help to generate new approaches for therapeutic interventions.

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1,437 Citations


Journal ArticleDOI: 10.1038/NATURE03952
15 Sep 2005-Nature
Abstract: Shear stress is a fundamental determinant of vascular homeostasis, regulating vascular remodelling, cardiac development and atherogenesis, but the mechanisms of transduction are poorly understood. Previous work showed that the conversion of integrins to a high-affinity state mediates a subset of shear responses, including cell alignment and gene expression. Here we investigate the pathway upstream of integrin activation. PECAM-1 (which directly transmits mechanical force), vascular endothelial cell cadherin (which functions as an adaptor) and VEGFR2 (which activates phosphatidylinositol-3-OH kinase) comprise a mechanosensory complex. Together, these receptors are sufficient to confer responsiveness to flow in heterologous cells. In support of the relevance of this pathway in vivo, PECAM-1-knockout mice do not activate NF-kappaB and downstream inflammatory genes in regions of disturbed flow. Therefore, this mechanosensing pathway is required for the earliest-known events in atherogenesis.

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Topics: Vascular remodelling in the embryo (55%), Signal transduction (53%), Cell signaling (52%) ... read more

1,387 Citations


Open accessJournal ArticleDOI: 10.1101/CSHPERSPECT.A006502
Sina Koch1, Lena Claesson-Welsh1Institutions (1)
Abstract: Vascular endothelial growth factors (VEGFs) are master regulators of vascular development and of blood and lymphatic vessel function during health and disease in the adult. It is therefore important to understand the mechanism of action of this family of five mammalian ligands, which act through three receptor tyrosine kinases (RTKs). In addition, coreceptors like neuropilins (NRPs) and integrins associate with the ligand/receptor signaling complex and modulate the output. Therapeutics to block several of the VEGF signaling components have been developed with the aim to halt blood vessel formation, angiogenesis, in diseases that involve tissue growth and inflammation, such as cancer. In this review, we outline the current information on VEGF signal transduction in relation to blood and lymphatic vessel biology.

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904 Citations


Journal ArticleDOI: 10.1038/NATURE09002
Yingdi Wang1, Masanori Nakayama2, Mara E. Pitulescu2, Tim S. Schmidt1  +14 moreInstitutions (6)
27 May 2010-Nature
Abstract: In development, tissue regeneration or certain diseases, angiogenic growth leads to the expansion of blood vessels and the lymphatic vasculature. This involves endothelial cell proliferation as well as angiogenic sprouting, in which a subset of cells, termed tip cells, acquires motile, invasive behaviour and extends filopodial protrusions. Although it is already appreciated that angiogenesis is triggered by tissue-derived signals, such as vascular endothelial growth factor (VEGF) family growth factors, the resulting signalling processes in endothelial cells are only partly understood. Here we show with genetic experiments in mouse and zebrafish that ephrin-B2, a transmembrane ligand for Eph receptor tyrosine kinases, promotes sprouting behaviour and motility in the angiogenic endothelium. We link this pro-angiogenic function to a crucial role of ephrin-B2 in the VEGF signalling pathway, which we have studied in detail for VEGFR3, the receptor for VEGF-C. In the absence of ephrin-B2, the internalization of VEGFR3 in cultured cells and mutant mice is defective, which compromises downstream signal transduction by the small GTPase Rac1, Akt and the mitogen-activated protein kinase Erk. Our results show that full VEGFR3 signalling is coupled to receptor internalization. Ephrin-B2 is a key regulator of this process and thereby controls angiogenic and lymphangiogenic growth.

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870 Citations