scholarly journals Fibronectin‐Mediated Inflammatory Signaling Through Integrin α5 in Vascular Remodeling

2021 ◽  
Author(s):  
Madhusudhan Budatha ◽  
Jiasheng Zhang ◽  
Martin A. Schwartz
Keyword(s):  
Endothelial Cells ◽  
Basement Membrane ◽  
Vascular Remodeling ◽  
Matrix Protein ◽  
Vascular Endothelial Cells ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Inflammatory Signaling ◽  
Carotid Ligation ◽  
Integrin Α5

Background Adhesion of vascular endothelial cells to the underlying basement membrane potently modulates endothelial cells to cells' inflammatory activation. The normal basement membrane proteins laminin and collagen IV attenuate inflammatory signaling in part through integrin α2β1. In contrast, fibronectin, the provisional matrix protein found in injured, remodeling or inflamed vessels, sensitizes endothelial cells to inflammatory stimuli through integrins α5β1and and αvβ3. A chimeric integrin in which the cytoplasmic domain of α5 is replaced with that of α2 pairs with β1 and binds fibronectin but signals like α2β1. Methods and Results Here, we examined mice in which integrin α5 is replaced with the α5/2 chimera, using the transverse aortic constriction and partial carotid ligation models of vessel remodeling. Following transverse aortic constriction and partial carotid ligation surgery, wild‐type mice showed increased fibronectin deposition and expression of inflammatory markers, which were strongly attenuated in a5/2 mice. α5/2 mice also showed reduced artery wall hypertrophy in the transverse aortic constriction model and diminished inward remodeling in the partial carotid ligation model. Acute atherosclerosis after partial carotid ligation in hyperlipidemic ApoE −/− mice on a high fat diet was dramatically decreased in α5/2 mice. Conclusions Fibronectin and integrin α5 signaling is a key element of pathological vascular remodeling in acute models of both hypertension and disturbed flow. These results underscore the key role for integrin α5 signaling in pathological vascular remodeling associated with hypertension and atherosclerosis and support its potential as a therapeutic target.

scholarly journals Fibronectin-mediated inflammatory signaling through integrin α5 in vascular remodeling

2021 ◽  
Author(s):  
Madhusudhan Budatha ◽  
Jiasheng Zhang ◽  
Martin A Schwartz
Keyword(s):  
Basement Membrane ◽  
Vascular Remodeling ◽  
Matrix Protein ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Inflammatory Signaling ◽  
Vessel Remodeling ◽  
Inflammatory Stimuli ◽  
Integrin Α5 ◽  
Fibronectin Deposition

Adhesion of vascular endothelial cells (ECs) to the underlying basement membrane potently modulates EC inflammatory activation. The normal basement membrane proteins laminin and collagen IV attenuate inflammatory signaling in part through integrin α2β1. In contrast, fibronectin, the provisional matrix protein found in injured, remodeling or inflamed vessels, sensitizes ECs to inflammatory stimuli through integrins α5β1and and αvβ3. A chimeric integrin in which the cytoplasmic domain of α5 is replaced with that of α2 pairs with β1 and binds fibronectin but signals like α2β1. Here, we examined mice in which integrin α5 is replaced with the α5/2 chimera, using the transverse aortic constriction (TAC) and partial carotid ligation (PCL) models of vessel remodeling. Following TAC and PCL surgery, WT mice showed increased fibronectin deposition and expression of inflammatory markers, which were strongly attenuated in a5/2 mice. α5/2 mice also showed reduced artery wall hypertrophy in the TAC model and diminished inward remodeling in the PCL model. Acute atherosclerosis after PCL in hyperlipidemic ApoE-/- mice on a high fat diet was dramatically decreased in α5/2 mice. These results underscore the key role for integrin α5 signaling in pathological vascular remodeling and support its potential as a therapeutic target.

1439PRAS40 attenuates mTOR-dependent endothelial inflammation and atherosclerosis

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
K Zhang ◽  
J Schecker ◽  
K Woeltje ◽  
A Krull ◽  
V Stangl ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mtor Inhibitors ◽  
Negative Regulation ◽  
Mtor Signaling ◽  
Adhesion Assay ◽  
Inflammatory Signaling ◽  
Endothelial Inflammation ◽  
Carotid Ligation ◽  
Mtorc1 Signaling ◽  
The Impact

Abstract Introduction Endothelial inflammation plays a pivotal role in atherosclerosis. Many inflammatory and metabolic signals converge upon mechanistic target of rapamycin (mTOR), and inhibition of mTOR has been shown to reduce atherosclerosis. However, clinical use of mTOR-inhibitors is limited by serious adverse effects, of which insulin resistance and dyslipidemia are particularly troubling in the context of atherosclerosis. In that respect, targeting PRAS40, an endogenous modulator of mTOR complex 1 (mTORC1) with highly cell type-specific effects on mTOR signaling, may be a more promising approach. In fact, we have previously demonstrated that, in contrast to conventional mTOR inhibitors, PRAS40 gene therapy substantially improves metabolic profile in obese mice. However, the function of PRAS40 in endothelial cells and its role in atherosclerosis have never been investigated. Methods and results To define the impact of PRAS40 on endothelial mTORC1-signaling in this context, cultured human umbilical vein endothelial cells (HUVECs) were exposed to the atherogenic cytokine TNFα. TNFα induced mTOR signaling as evidenced by increased phosphorylation of S6 kinase and ribosomal S6 protein. Interestingly, this effect was strongly augmented upon siRNA-mediated knock-down of PRAS40, indicating a negative regulation of mTORC1 by PRAS40 in endothelial cells. Moreover, PRAS40-knockdown promoted TNFα-induced inflammatory signaling as reflected by increased proliferative activity, upregulation of atherogenic markers like CCL2 and VCAM-1, as well as enhanced monocyte recruitment in the THP-1 adhesion assay. In contrast, PRAS40-overexpression blocked TNFα-induced activation of mTORC1 and consistently suppressed all of these measures of inflammatory activation. All effects of PRAS40-overexpression could be reproduced by the mTORC1 inhibitors rapamycin and torin1. Thus, our in vitro studies suggest that in endothelial cells PRAS40 exerts anti-atherogenic effects by negative regulation of mTORC1. To validate these findings in vivo in the context of atherosclerosis we created transgenic mice with tamoxifen-inducible endothelium-specific PRAS40-deficiency (EC-PRAS40-KO). These mice were exposed to a model of accelerated atherosclerosis based on western diet and partial carotid ligation: Four weeks after partial carotid ligation, neointimal and atherosclerotic lesion formation was strongly enhanced in EC-PRAS40-KO mice. Moreover, mTORC1 activity as well as CCL2 and VCAM-1 expression were markedly increased compared to control mice. Conclusion Our data indicate that PRAS40 suppresses atherosclerosis via inhibition of mTORC1-mediated inflammatory signaling in endothelial cells. In conjunction with its favourable effects on metabolic homeostasis, the overall therapeutic profile of PRAS40-treatment appears to be beneficial compared to conventional mTOR-inhibitors. Taken together PRAS40 may qualify as a promising therapeutic target for the treatment of atherosclerosis. Acknowledgement/Funding German Federal Ministry of Education and Research, DZHK (German Centre for Cardiovascular Research)

High Shear Stress Induces Production of Matrix Metalloproteinase in Endothelial Cells

2008 ◽  
Author(s):  
Naoya Sakamoto ◽  
Toshiro Ohashi ◽  
Masaaki Sato
Keyword(s):  
Endothelial Cells ◽  
Vascular Remodeling ◽  
Vascular Endothelial Cells ◽  
Elastic Fibers ◽  
Vascular Endothelial ◽  
High Shear ◽  
Tissue Inhibitor Of Metalloproteinases ◽  
High Shear Stress ◽  
Arterial Aneurysms ◽  
Specific Inhibitors

One of the major physiological functions of vascular endothelial cells (ECs) includes remodeling of vessel walls. ECs secrete matrix metalloproteinases (MMPs) to degrade extracellular matrix (ECM), such as elastin and collagen. At least 23 different MMPs have been identified and have the capacity to degrade components of ECM. For example, MMP-9, known as a gelatinase, can degrade elastic fibers. The balance between MMPs and their specific inhibitors, tissue inhibitor of metalloproteinases (TIMPs), tightly governs vascular remodeling and is belived to play a central role in the pathogenesis of arterial aneurysms [1].

scholarly journals Pericyte-derived vitronectin regulates blood-CNS barrier function via integrin signaling

2021 ◽  
Author(s):  
Swathi Ayloo ◽  
Christopher Gallego Lazo ◽  
Shenghuan Sun ◽  
Wei Zhang ◽  
Bianxiao Cui ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Barrier Function ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Integrin Signaling ◽  
Integrin Receptor ◽  
Perivascular Cells ◽  
Extrinsic Factors ◽  
Genetic Ablation ◽  
Integrin Α5

Blood-central nervous system (CNS) barriers are physiological interfaces separating the neural tissue from circulating blood and are essential for neuronal function and cellular homeostasis. Endothelial cells that form the walls of CNS blood vessels constitute these barriers but barrier properties are not intrinsic to these cells; rather they are actively induced and maintained by the surrounding CNS microenvironment. Notably, the abluminal surface of CNS capillary endothelial cells is ensheathed by pericytes and astrocytic endfeet. However, the specific extrinsic factors from these perivascular cells that regulate barrier integrity are largely unknown. Here, we establish vitronectin, an extracellular matrix protein secreted specifically by CNS pericytes as an essential factor in regulating blood-CNS barrier function via interactions with its integrin receptor in adjacent endothelial cells. Genetic ablation of vitronectin results in leaky blood-CNS barriers, despite having normal pericyte coverage and vascular patterning. Electron microscopy reveals increased transcytosis in endothelial cells of Vtn−/− mice without functional defects in tight-junctions. We further demonstrate that vitronectin binding to integrin receptors is essential for barrier function, as mice harboring a point mutation in vitronectin that specifically abolishes integrin binding, VtnRGE, phenocopy the barrier defects in Vtn−/− mice. Furthermore, endothelial-specific deletion of integrin α5, an RGD-ligand binding integrin receptor that is expressed in CNS endothelial cells, also results in similar blood-CNS barrier defects as observed in Vtn−/− and VtnRGE mice. Finally, integrin α5 activation by vitronectin inhibits transcytosis in endothelial cells and vitronectin-integrin α5 signaling regulates barrier function independent of the caveolae pathway. These results demonstrate that signaling from perivascular cells to endothelial cells via ligand-receptor interactions is a key mechanism to regulate barrier permeability.SummaryVitronectin-integrin signaling between pericytes and CNS endothelial cells regulates blood-CNS barrier function

New paradigms in inflammatory signaling in vascular endothelial cells

2014 ◽  
Vol 306 (3) ◽  
pp. H317-H325 ◽  
Author(s):  
Lei Xiao ◽  
Yahan Liu ◽  
Nanping Wang
Keyword(s):  
Endothelial Cells ◽  
Cardiovascular Diseases ◽  
Inflammatory Response ◽  
Vascular Endothelial Cells ◽  
Nuclear Factor Κb ◽  
Membrane Receptors ◽  
Vascular Endothelial ◽  
Intercellular Signaling ◽  
Inflammatory Signaling ◽  
New Class

Inflammation is a basic cellular process in innate and adaptive immunity. Vascular endothelial cells play an important role in the initiation, amplification, and resolution of the inflammatory response. Deregulated inflammatory response is implicated in a variety of cardiovascular diseases such as atherosclerosis, obesity, diabetes, and hypertension. Recent studies have made significant progresses in the understanding of the complex molecular pathways that mediate the pro- and anti-inflammatory signaling in endothelial cells (ECs). Specifically, a number of macromolecular complexes termed as signalosomes have been identified to integrate the proinflammatory signaling from the membrane receptors to key transcription factors such as nuclear factor-κB (NF-κB). Inflammasomes are associated with the pattern-recognition receptors such as Toll-like receptors (TLRs), nucleotide-binding oligomerization-domain (NOD)-like receptors (NLRs) to mediate innate immunity responses. Emerging evidence has also revealed that noncoding microRNAs constitute a new class of intra- and intercellular signaling molecules to modulate inflammation in ECs. Thus this article will briefly summarize these new mechanisms with a special emphasis in the context of cardiovascular diseases.

scholarly journals Cardiac Microvascular Endothelial Cells in Pressure Overload–Induced Heart Disease

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Sander Trenson ◽  
Hadewich Hermans ◽  
Sander Craps ◽  
Peter Pokreisz ◽  
Pauline de Zeeuw ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Left Ventricle ◽  
Functional Status ◽  
Right Atrium ◽  
Pressure Overload ◽  
Outflow Tract ◽  
Microvascular Endothelial Cells ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Microvascular Endothelial

Background: Chronic pressure overload predisposes to heart failure, but the pathogenic role of microvascular endothelial cells (MiVEC) remains unknown. We characterized transcriptional, metabolic, and functional adaptation of cardiac MiVEC to pressure overload in mice and patients with aortic stenosis (AS). Methods: In Tie2-Gfp mice subjected to transverse aortic constriction or sham surgery, we performed RNA sequencing of isolated cardiac Gfp + -MiVEC and validated the signature in freshly isolated MiVEC from left ventricle outflow tract and right atrium of patients with AS. We next compared their angiogenic and metabolic profiles and finally correlated molecular and pathological signatures with clinical phenotypes of 42 patients with AS (50% women). Results: In mice, transverse aortic constriction induced progressive systolic dysfunction, fibrosis, and reduced microvascular density. After 10 weeks, 25 genes predominantly involved in matrix-regulation were >2-fold upregulated in isolated MiVEC. Increased transcript levels of Cartilage Intermediate Layer Protein ( Cilp ), Thrombospondin-4 , Adamtsl-2 , and Collagen1a1 were confirmed by quantitative reverse transcription polymerase chain reaction and recapitulated in left ventricle outflow tract-derived MiVEC of AS ( P <0.05 versus right atrium-MiVEC). Fatty acid oxidation increased >2-fold in left ventricle outflow tract-MiVEC, proline content by 130% (median, IQR, 58%–474%; P =0.008) and procollagen secretion by 85% (mean [95% CI, 16%–154%]; P <0.05 versus right atrium-MiVEC for all). The altered transcriptome in left ventricle outflow tract-MiVEC was associated with impaired 2-dimensional-vascular network formation and 3-dimensional-spheroid sprouting ( P <0.05 versus right atrium-MiVEC), profibrotic ultrastructural changes, and impaired diastolic left ventricle function, capillary density and functional status, especially in female AS. Conclusions: Pressure overload induces major transcriptional and metabolic adaptations in cardiac MiVEC resulting in excess interstitial fibrosis and impaired angiogenesis. Molecular rewiring of MiVEC is worse in women, compromises functional status, and identifies novel targets for intervention.

scholarly journals Renal Expression of the Ets-1 Proto-oncogene during Progression of Rat Crescentic Glomerulonephritis

2000 ◽  
Vol 11 (12) ◽  
pp. 2243-2255
Author(s):  
TAKASHI NAITO ◽  
MOHAMMED S. RAZZAQUE ◽  
ARIFA NAZNEEN ◽  
DIANGE LIU ◽  
HIROSHI NIHEI ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Basement Membrane ◽  
Glomerular Basement Membrane ◽  
Crescentic Glomerulonephritis ◽  
Vascular Endothelial Cells ◽  
Immunohistochemical Analysis ◽  
Glomerular Diseases ◽  
Reverse Transcription Pcr ◽  
Matrix Metalloproteinase 1 ◽  
Type Plasminogen Activator

Abstract. The ets-1 proto-oncogene is a member of the transcriptional factor family and was identified by homology to the v-ets oncogene. It was recently demonstrated that Ets-1 protein interacts with the promoter region of the genes coding for proteinases, including matrix metalloproteinase-1 (MMP-1), MMP-3, and urokinase-type plasminogen activator, suggesting that it may play an important role in the regulation of MMP expression. The role of the ets-1 proto-oncogene in advanced glomerular diseases, where extracellular matrix accumulation is observed, remains undefined. In this study, the expression of ets-1 mRNA and protein during the progression of rat crescentic glomerulonephritis was examined using immunohistochemical analysis, reverse transcription-PCR, and in situ hybridization. Passive accelerated anti-glomerular basement membrane-induced nephritis was induced in rats by intravenous injection of nephrotoxic serum. Rats were euthanized on day 7, 14, 21, 28, or 42. Immunohistochemical analysis demonstrated significant upregulation of Ets-1 protein expression in glomeruli and the interstitium in anti-glomerular basement membrane-induced nephritis. The numbers of Ets-1-positive cells were increased 8.8-fold on day 21 in glomeruli (1.2 ± 0.1 cells/glomerular cross-section, P < 0.001) and sixfold on day 28 in the interstitium (21 ± 1.3 cells/mm2, P < 0.001), compared with control samples. Ets-1 protein was predominantly localized in glomerular epithelial cells, endothelial cells, and interstitial cells. A small number of vascular endothelial cells, macrophages, and T cells also expressed Ets-1 protein. MMP-3 deposition was upregulated and positive cells in the interstitium often coexpressed Ets-1, whereas only a few glomerular cells were positive for both MMP-3 and Ets-1 protein. The expression of ets-1 mRNA was also markedly increased in diseased kidneys. The distribution of ets-1 mRNA was similar to that of the protein. These results indicate that overexpression of the ets-1 proto-oncogene by phenotypically altered renal cells might be associated with the pathogenesis of rat crescentic glomerulonephritis.

scholarly journals Effects of High Glucose on the Expression of LAMA1 and Biological Behavior of Choroid Retinal Endothelial Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Guangwei Song ◽  
Da Lin ◽  
Licheng Bao ◽  
Qi Jiang ◽  
Yinan Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Basement Membrane ◽  
High Glucose ◽  
Vascular Endothelial Cells ◽  
Primary Component ◽  
Biological Behavior ◽  
Major Protein ◽  
Vascular Endothelial ◽  
Rt Pcr

Hyperglycemia is one of the main causes of proliferative diabetic retinopathy (PDR) characterized by thickening of the vascular basement membrane. Laminin alpha 1 (LAMA1) is a primary component of laminin, a major protein constituent of the basement membrane. In this study, we investigated the role of LAMA1 in the development of PDR. Retinal choroidal vascular endothelial cells (RF/6A line) were exposed to glucose at different concentrations (5 mM, 15 mM, 25 mM, and 35 mM) and analyzed for cell growth, migration, proliferation, and adhesion. LAMA1 expression was examined 24 and 48 h following glucose treatment using Western blotting, RT-PCR, and immunofluorescence. The results showed that the proliferation, migration, and adhesion of RF/6A cells were increased by high glucose, whereas LAMA1 expression was slightly higher at 15 mM but decreased at 25 mM and 35 mM glucose compared to control. Thus, the changes in the biological behavior of high glucose-exposed retinal vascular endothelial cells correspond to variations in LAMA1 expression, indicating a possibility for LAMA1 involvement in PDR development. Our findings suggest that LAMA1 may play a role in PDR and, thus, may serve as a potential target for DR diagnosis and/or treatment.

scholarly journals Basement membrane-like structures containing NTH α1(IV) are formed around the endothelial cell network in a novel in vitro angiogenesis model

2019 ◽  
Vol 317 (2) ◽  
pp. C314-C325
Author(s):  
Yongchol Shin ◽  
Akane Moriya ◽  
Yuta Tohnishi ◽  
Takafumi Watanabe ◽  
Yasutada Imamura
Keyword(s):  
Endothelial Cells ◽  
Basement Membrane ◽  
Blood Vessels ◽  
Type Iv Collagen ◽  
Vascular Endothelial Cells ◽  
Culture Dish ◽  
Cell Network ◽  
Type Iv

Angiogenesis is a process through which new blood vessels are formed by sprouting and elongating from existing blood vessels. Several methods have been used to replicate angiogenesis in vitro, including culturing vascular endothelial cells on Matrigel and coculturing with endothelial cells and fibroblasts. However, the angiogenesis elongation process has not been completely clarified in these models. We therefore propose a new in vitro model of angiogenesis, suitable for observing vascular elongation, by seeding a spheroid cocultured from endothelial cells and fibroblasts into a culture dish. In this model, endothelial cells formed tubular networks elongated from the spheroid with a lumen structure and were connected with tight junctions. A basement membrane (BM)-like structure was observed around the tubular network, similarly to blood vessels in vivo. These results suggested that blood vessel-like structure could be reconstituted in our model. Laminin and type IV collagen, main BM components, were highly localized around the network, along with nontriple helical form of type IV collagen α1-chain [NTH α1(IV)]. In an ascorbic acid-depleted condition, laminin and NTH α1(IV) were observed around the network but not the triple-helical form of type IV collagen and the network was unstable. These results suggest that laminin and NTH α1(IV) are involved in the formation of tubular network and type IV collagen is necessary to stabilize the network.

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