scholarly journals Fibrinogen-Induced Increased Pial Venular Permeability in Mice

2011 ◽  
Vol 32 (1) ◽  
pp. 150-163 ◽  
Author(s):  
Nino Muradashvili ◽  
Natia Qipshidze ◽  
Charu Munjal ◽  
Srikanth Givvimani ◽  
Richard L Benton ◽  
...  
Keyword(s):  
Blood Level ◽  
Gene Knockout ◽  
Vascular Dysfunction ◽  
Fluorescein Isothiocyanate ◽  
Vascular Endothelial ◽  
Elevated Blood ◽  
Vascular Endothelial Cadherin ◽  
Cerebrovascular Dysfunction ◽  
Cerebrovascular Permeability ◽  
Phosphate Buffered Saline

Elevated blood level of Fibrinogen (Fg) is commonly associated with vascular dysfunction. We tested the hypothesis that at pathologically high levels, Fg increases cerebrovascular permeability by activating matrix metalloproteinases (MMPs). Fibrinogen (4 mg/mL blood concentration) or equal volume of phosphate-buffered saline (PBS) was infused into male wild-type (WT; C57BL/6J) or MMP-9 gene knockout (MMP9-/-) mice. Pial venular leakage of fluorescein isothiocyanate-bovine serum albumin to Fg or PBS alone and to topically applied histamine (105mol/L) were assessed. Intravital fluorescence microscopy and image analysis were used to assess cerebrovascular protein leakage. Pial venular macromolecular leakage increased more after Fg infusion than after infusion of PBS in both (WT and MMP9-/-) mice but was more pronounced in WT compared with MMP9-/-mice. Expression of vascular endothelial cadherin (VE-cadherin) was less and plasmalemmal vesicle-associated protein-1 (PV-1) was greater in Fg-infused than in PBS-infused both mice groups. However, in MMP9-/-mice, VE-cadherin expression was greater and PV-1 expression was less than in WT mice. These data indicate that at higher levels, Fg compromises microvascular integrity through activation of MMP-9 and downregulation of VE-cadherin and upregulation of PV-1. Our results suggest that elevated blood level of Fg could have a significant role in cerebrovascular dysfunction and remodeling.

Stealthy Nanoparticles Protecting Endothelium Barrier from Leakiness by Resisting the Absorption of VE-cadherin

Nanoscale ◽  
2021 ◽  
Author(s):  
Yuan Huang ◽  
Suxiao Wang ◽  
Jin-Zhi Zhang ◽  
Hang-Xing Wang ◽  
Qichao Zou ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Interstitial Space ◽  
Cell Interactions ◽  
Vascular Endothelial ◽  
Vascular Endothelial Cadherin ◽  
Cell Cell

Nanomaterial induced endothelial cells leakiness (NanoEL) is caused because nanomaterials enter the interstitial space of endothelial cells and disrupt the endothelial cell-cell interactions by interacting with vascular endothelial cadherin (VE-cad)....

scholarly journals sFLT-1 inhibits proliferation, migration, and invasion of colorectal cancer SW480 cells through vascular mimicry formation suppression

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831769833 ◽  
Author(s):  
Wang Jinjun ◽  
Wang Zhaowei ◽  
Li Qiang ◽  
Xue Zhijun ◽  
Zhang Juanzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tyrosine Kinase ◽  
Three Dimensional ◽  
New Drugs ◽  
Migration And Invasion ◽  
Vascular Endothelial ◽  
Three Dimensional Model ◽  
Vascular Endothelial Cadherin ◽  
Sw480 Cells ◽  
Vascular Mimicry

To investigate the effects of soluble fms-like tyrosine kinase-1 on the vascular mimicry formation, proliferation, migration, and invasion of colorectal cancer SW480 cells. The recombinant plasmid pBLAST49-sFLT-1 or pBLAST49 control plasmid was transfected into SW480 cells to obtain hsFLT-1-SW480 or Ctrl-SW480 cells. The three-dimensional model culture, sulforhodamine B assay, scratch assay, and Transwell assay were performed to detect the vascular mimicry formation, proliferation, migration, and invasion of colorectal cancer SW480 cells, respectively. Western blotting was used to detect the expression of vascular endothelial–cadherin protein. Compared with Ctrl-SW480 cells, vascular mimicry formation ((0.85 ± 0.04) vs (7.40 ± 0.69), p < 0.05) and vascular endothelial–cadherin expression ((1.25 ± 0.08) vs (1.89 ± 0.03), p < 0.05) were significantly decreased, and the growth rate was also significantly decreased in hsFLT-1-SW480 cells ((32.54 ± 5.12) vs (88.13 ± 11.52), p < 0.05). Moreover, the migration ((0.46 ± 0.08) vs (0.94 ± 0.03), p < 0.05) and invasion capacity ((59.14 ± 3.64) vs (134.85 ± 10.16), p < 0.05) of SW480 cells were significantly inhibited upon soluble fms-like tyrosine kinase-1 transfection. soluble fms-like tyrosine kinase-1 inhibits cell proliferation, migration, and invasion of colorectal cancer SW480 cells through suppression of vascular mimicry formation, which provides a good basis for the development of new drugs for the treatment of colorectal cancer by targeting both angiogenesis and vascular mimicry formation.

scholarly journals Synergy between Extracellular Modules of Vascular Endothelial Cadherin Promotes Homotypic Hexameric Interactions

2002 ◽  
Vol 277 (15) ◽  
pp. 12790-12801 ◽  
Author(s):  
Stéphanie Bibert ◽  
Michel Jaquinod ◽  
Evelyne Concord ◽  
Christine Ebel ◽  
Elizabeth Hewat ◽  
...  
Keyword(s):  
Vascular Endothelial ◽  
Vascular Endothelial Cadherin

Abstract 212: Role of Monocytes and Inflammation in Vascular Endothelial Dysfunction in Mice With Heart Failure After Myocardial Infarction

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Michael Molitor ◽  
Stefanie Finger ◽  
Sabine Kossmann ◽  
Venkata S Garlapati ◽  
Jérémy Lagrange ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Muscle Function ◽  
Diphtheria Toxin ◽  
Vascular Dysfunction ◽  
Aortic Tissue ◽  
Vascular Endothelial ◽  
Smooth Muscle Function ◽  
Myelomonocytic Cells

Background: Heart failure (HF) after myocardial infarction (MI) leads to impaired left ventricular function and reduced blood flow in peripheral arteries. Angiotensin II (ATII) signaling is crucial in MI, and inflammatory myelomonocytic cells are involved in the process of ATII-induced vascular dysfunction. Their role in MI-mediated vascular dysfunction has not been defined yet. Objective: Test the impact of selective depletion of lysozyme M positive (LysM+) myelomonocytic cells on endothelial dysfunction in a model of ischemic heart failure in mice Methods and results: 8 to 12 week old mice (C57B6 background) were subjected to permanent coronary ligation of the left anterior descending artery (LAD) to induced HF post MI. We measured a reduced vascular endothelial and smooth muscle function in isolated aortic segments 7d and 28d post MI in isometric tension studies. Also the production of vascular superoxide (chemiluminescence, oxidative fluorescence microtopography) and vascular mRNA expression of MCP-1, VCAM-1, IL-6 and ATII receptor type 1 were increased (assessed by mRNA reverse transcription polymerase chain reaction) in HF mice compared to sham. FACS analysis of aortic tissue of HF mice shows an increased infiltration of CD45+ immune cells in the aortic wall, including CD11b+Gr-1lowF4/80+ monocytes/macrophages. Using mice with LysM dependent cre-inducible expression of diphtheria toxin receptor (LysMCreIDTR) we selectively ablated LysM+ myelomonocytic cells 28d after MI for 10d via diphtheria toxin. We assessed a significantly improved vascular endothelial and smooth muscle function, less vascular superoxide production and a reduced expression of VCAM-1 and ATII receptor type 1 in aortic tissue. The number of circulating monocytes in blood was reduced, while the cardiac function (EF (%), LV size) in sonography stays constant between depleted and non-depleted HF mice. Conclusion: Our results suggest that vascular dysfunction post MI is at least in part mediated by inflammatory leukocyte infiltrating the vessel wall and that depletion of inflammatory monocytes in HF after MI improves the vascular function. It can potentially be a new target to protect endothelial function in HF and prevent secondary events after a MI.

Abstract 13383: The Vascular Endothelial Barrier: A Novel Therapeutic Target for Preventing Atrial Fibrillation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Louisa Mezache ◽  
Heather Struckman ◽  
Anna Phillips ◽  
Stephen Baine ◽  
Amara Greer-short ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ex Vivo ◽  
Vascular Dysfunction ◽  
Super Resolution ◽  
Vascular Endothelial ◽  
Vascular Leak ◽  
Barrier Breakdown ◽  
Endothelial Growth Factor ◽  
Intercalated Disk

Atrial fibrillation (AF), the most common arrhythmia, is associated with inflammation and vascular dysfunction. AF patients have elevated levels of vascular endothelial growth factor (VEGF; 90-580 pg/ml), which promotes vascular leak and edema. We have previously identified edema-induced disruption of sodium channel (Na V 1.5) -rich intercalated disk (ID) nanodomains as a novel arrhythmia mechanism. We hypothesized that (i) elevated VEGF levels promote AF by disrupting ID nanodomains, and slowing atrial conduction, and (ii) protection of the vascular barrier can prevent these arrhythmias. Clinically-relevant VEGF levels (500 pg/ml, 60 minutes) increased FITC-dextran extravasation (99.3% vs. 24.3% in vehicle controls) in WT mouse hearts, consistent with increased vascular leak. Electron microscopy revealed ID nanodomain swelling, near both gap junctions (perinexi; 64±9nm vs 17±1nm) and mechanical junctions (63±4nm vs 27±2nm) in VEGF-treated hearts relative to controls. Super-resolution STORM microscopy revealed Na V 1.5 enrichment at perinexi (9±2 fold) and N-cadherin-rich sites (7±1 fold) relative to non-junctional ID sites in control hearts. VEGF reduced Na V 1.5 enrichment at both sites (6±1 and 4±1 fold, respectively), consistent with Na V 1.5 translocation from ID nanodomains. Atrial conduction, assessed by optical mapping, was slowed by VEGF (10±0.4 cm/s vs 21.3±1.3 cm/s at baseline). VEGF increased atrial arrhythmia burden both ex vivo (80% vs 0% in vehicle controls) and in vivo (70% vs 20% in vehicle controls). Next, we tested two strategies shown to prevent vascular barrier breakdown. Blocking connexin43 hemichannels (αCT11 peptide) decreased both incidence (40%) and duration (1.45±3.42s) of VEGF-induced arrhythmias. Likewise, blocking pannexin1 channels (Panx1-IL2 peptide) shortened VEGF-induced arrhythmias (2.48±0.83s). Mefloquine and spironolactone, which are small molecules that respectively inhibit Cx43 hemichannels and pannexin channels, were also found to effectively prevent VEGF-induced atrial arrhythmias. These results highlight VEGF-induced vascular leak as a novel mechanism for AF, and suggest vascular barrier protection as an anti-arrhythmic strategy.

Sign in / Sign up

Export Citation Format

Share Document