scholarly journals Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability

2021 ◽  
Author(s):  
Li Wang ◽  
Matteo Astone ◽  
Sk. Kayum Alam ◽  
Zhu Zhu ◽  
Wuhong Pei ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Intercellular Adhesion Molecule ◽  
Vascular Endothelial ◽  
Intercellular Adhesion Molecule 1 ◽  
Potent Inducer ◽  
Stat3 Signaling ◽  
Integral Role ◽  
Tissue Recovery ◽  
Endothelial Growth Factor ◽  
Transcription 3

Vascular permeability triggered by inflammation or ischemia promotes edema, exacerbates disease progression, and impairs tissue recovery. Vascular endothelial growth factor (VEGF) is a potent inducer of vascular permeability. VEGF plays an integral role in regulating vascular barrier function physiologically and in pathologies, including cancer, stroke, cardiovascular disease, retinal conditions, and COVID-19-associated pulmonary edema, sepsis, and acute lung injury. Understanding temporal molecular regulation of VEGF-induced vascular permeability will facilitate developing therapeutics to inhibit vascular permeability, while preserving tissue-restorative angiogenesis. Here, we demonstrate that VEGF signals through signal transducer and activator of transcription 3 (STAT3) to promote vascular permeability. We show that genetic STAT3 ablation reduces vascular permeability in STAT3-deficient endothelium of mice and VEGF-inducible zebrafish crossed with CRISPR/Cas9 generated Stat3 knockout zebrafish. Intercellular adhesion molecule 1 (ICAM-1) expression is transcriptionally regulated by STAT3 and VEGF-dependent STAT3 activation is regulated by JAK2. Pyrimethamine, an FDA-approved anti-microbial agent that inhibits STAT3-dependent transcription, substantially reduces VEGF-induced vascular permeability in zebrafish, mouse, and human endothelium. Collectively, our findings suggest that VEGF/VEGFR-2/JAK2/STAT3 signaling regulates vascular barrier integrity, and inhibition of STAT3-dependent activity reduces VEGF-induced vascular permeability.

scholarly journals Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability

2020 ◽  
Author(s):  
Li Wang ◽  
Matteo Astone ◽  
Sk. Kayum Alam ◽  
Zhu Zhu ◽  
Wuhong Pei ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Intercellular Adhesion Molecule ◽  
List Type ◽  
Intercellular Adhesion Molecule 1 ◽  
Potent Inducer ◽  
Barrier Integrity ◽  
Tissue Recovery ◽  
And Function ◽  
Vascular Barrier Integrity

ABSTRACTVascular permeability triggered by inflammation or ischemia promotes edema, exacerbates disease progression, and impairs tissue recovery. Vascular endothelial growth factor (VEGF) is a potent inducer of vascular permeability. VEGF plays an integral role in regulating vascular barrier function physiologically and in pathologies, such as cancer, ischemic stroke, cardiovascular disease, retinal conditions, and COVID-19-associated pulmonary edema and sepsis, which often leads to acute lung injury, including acute respiratory distress syndrome. However, after initially stimulating permeability, VEGF subsequently mediates angiogenesis to repair damaged tissue. Consequently, understanding temporal molecular regulation of VEGF-induced vascular permeability will facilitate developing therapeutics that achieve the delicate balance of inhibiting vascular permeability while preserving tissue repair. Here, we demonstrate that VEGF signals through signal transducer and activator of transcription 3 (STAT3) to promote vascular permeability. Specifically, we show that genetic STAT3 ablation reduces vascular permeability in STAT3-deficient endothelium of mice and VEGF-inducible zebrafish crossed with CRISPR/Cas9 generated genomic STAT3 knockout zebrafish. Importantly, STAT3 deficiency does not impair vascular development and function in vivo. We identify intercellular adhesion molecule 1 (ICAM-1) as a STAT3-dependent transcriptional regulator and show VEGF-dependent STAT3 activation is regulated by JAK2. Pyrimethamine, an FDA-approved anti-microbial agent that inhibits STAT3-dependent transcription, substantially reduces VEGF-induced vascular permeability in zebrafish, mouse, and human endothelium. Indeed, pharmacologically targeting STAT3 increases vascular barrier integrity using two additional compounds, atovaquone and C188-9. Collectively, our findings suggest that the VEGF, VEGFR-2, JAK2, and STAT3 signaling cascade regulates vascular barrier integrity, and inhibition of STAT3-dependent activity reduces VEGF-induced vascular permeability in vertebrate models.Key PointsGenetic STAT3 deficiency in VEGF-inducible zebrafish and mice reveals that VEGF signals through STAT3 to promote vascular permeabilityPyrimethamine, a clinically available agent that inhibits STAT3 activity, reduces VEGF-induced vascular permeability in preclinical models

IL6 rs1800795 SNP may relate to cardiovascular pathology in alcohol abusers

2021 ◽  
pp. 30-42
Author(s):  
Д.И. Перегуд ◽  
В.Ю. Баронец ◽  
А.С. Лобачева ◽  
А.С. Иванов ◽  
И.В. Гармаш ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Clinical Manifestations ◽  
Serum Levels ◽  
Intercellular Adhesion Molecule ◽  
Vascular Endothelial ◽  
Intercellular Adhesion Molecule 1 ◽  
Alcohol Abusers ◽  
Cardiovascular Pathology ◽  
Genetically Determined ◽  
Endothelial Growth Factor

Формирование сердечно-сосудистой патологии при чрезмерном употреблении алкоголя сопряжено с повышением концентрации в крови таких медиаторов воспаления, как интерлейкины 6 (IL6) и 8 (IL8) и хемоаттрактанта моноцитов CCL2 (C-C motif ligand 2), а также молекул, участвующих в функционировании эндотелия, в частности фактора роста сосудистого эндотелия (VEGFA, vascular endothelial growth factor А), молекулы клеточной адгезии (ICAM1, intercellular adhesion molecule 1) и эндотелина (EDN1). Предполагается, что данный процесс генетически детерминирован, однако до настоящего момента исследований в этом направлении не проводилось. Целью работы явилось изучение ассоциации носительства аллелей полиморфных локусов, расположенных в генах IL6 (rs1800795), IL8 (rs4073), CCL2 (rs1024611), VEGFA (rs699947 и rs2010963), ICAM1 (rs281437) и EDN1 (rs1800541) с содержанием соответствующих полипептидов в циркуляторном русле и развитием сердечно-сосудистых заболеваний на фоне хронического злоупотребления алкоголем. В исследование были включены лица, злоупотребляющие алкоголем, без выраженной соматической патологии, а также пациенты, у которых на фоне злоупотребления развились заболевания сердечно-сосудистой системы. Уровень IL6, IL8, CCL2, VEGFA, ICAM1 и EDN1 в сыворотке крови оценивали посредством ИФА. Аллели полиморфных локусов были определены посредством ПЦР в режиме реального времени. Установлено, что среди лиц, злоупотребляющих алкоголем, с клинически выраженной патологией сердечно-сосудистой системы значительно чаще встречаются только носители гомозиготного генотипа GG или аллеля G полиморфного локуса в гене IL6 (rs1800795). Кроме того, носительство генотипа GG повышает вероятность развития сердечно-сосудистых заболеваний при хроническом злоупотреблении алкоголем. Однако, дополнительное влияние оказывают демографические факторы и клинические характеристики пациентов. В частности, введение поправки на возраст и пол, а также учет наличия цирроза печени, гипертензии и сахарного диабета, сопровождающих злоупотребление алкоголем, нивелируют повышение риска патологии сердечно-сосудистой системы. Ассоциации полиморфных вариантов в генах IL6 (rs1800795), IL8 (rs4073), CCL2 (rs1024611), VEGFA (rs699947 и rs2010963), ICAM1 (rs281437) и EDN1 (rs1800541) с содержанием белковых продуктов соответствующих генов в циркуляторном русле выявлено не было. Cardiovascular diseases in alcohol abusers are associated with elevation of plasma levels of proinflammatory cytokines such as IL6, IL8 and CCL2 as well as molecules involved in endothelial functioning including VEGFA, ICAM1 and EDN1. This phenomenon is supposed to be genetically determined. However to date the issue has not been investigated. Thus, we aimed to study the relationship between carriage of SNPs of IL6 (rs1800795), IL8 (rs4073), CCL2 (rs1024611), VEGFA (rs699947 and rs2010963), ICAM1 (rs281437) and EDN1 (rs1800541) genes with the serum levels of their products and the development of cardiovascular diseases in alcohol abusers. The study included alcohol abusers without apparent somatic pathology and alcohol abusers with clinical manifestations of cardiovascular disease. Serum levels of IL6, IL8, CCL2, VEGFA, ICAM1 and EDN1 were estimated by EIA. SNPs were determined by means of real-time PCR. We found that among the SNPs studied only carriers of homozygous GG genotype and G allele of IL6 (rs1800795) were more frequent in alcohol abusers with cardiovascular diseases. Moreover, carriage of homozygous GG genotype of IL6 (rs1800795) increases the probability of development of cardiovascular pathology in alcohol abusers. However, adjustment for age, gender and the presence of liver cirrhosis, hypertension and diabetes mellitus as co-variates eliminates the enhanced risk of cardiovascular pathology. Polymorphisms of IL6 (rs1800795), IL8 (rs4073), CCL2 (rs1024611), VEGFA (rs699947 and rs2010963), ICAM1 (rs281437) and EDN1 (rs1800541) did not determine serum levels of the related polypeptides.

scholarly journals Pharmacogenetics in Model-Based Optimization of Bevacizumab Therapy for Metastatic Colorectal Cancer

2020 ◽  
Vol 21 (11) ◽  
pp. 3753 ◽  
Author(s):  
Apostolos Papachristos ◽  
Eleni Karatza ◽  
Haralabos Kalofonos ◽  
Gregory Sivolapenko
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Clinical Outcomes ◽  
Biological Process ◽  
Mixed Effects ◽  
Intercellular Adhesion Molecule ◽  
Vascular Endothelial ◽  
Intercellular Adhesion Molecule 1 ◽  
Mixed Effects Modeling ◽  
Endothelial Growth Factor

Vascular endothelial growth factor A (VEGF-A) and intercellular adhesion molecule 1 (ICAM-1) are significant regulators of angiogenesis, an important biological process involved in carcinogenesis. Bevacizumab, an anti-VEGF monoclonal antibody (MAB), is approved for the treatment of metastatic Colorectal cancer (mCRC), however clinical outcomes are highly variable. In the present study, we developed a pharmacokinetic (PK), a simplified quasi-steady state (QSS) and a pharmacokinetic/pharmacodynamic (PK/PD) model to identify potential sources of variability. A total of 46 mCRC patients, who received bevacizumab in combination with chemotherapy were studied. VEGF-A (rs2010963, rs1570360, rs699947) and ICAM-1 (rs5498, rs1799969) genes’ polymorphisms, age, gender, weight, and dosing scheme were investigated as possible co-variates of the model’s parameters. Polymorphisms, trough, and peak levels of bevacizumab, and free VEGF-A were determined in whole blood and serum. Data were analyzed using nonlinear mixed-effects modeling. The two-compartment PK model showed that clearance (CL) was significantly lower in patients with mutant ICAM-1 rs1799969 (p < 0.0001), inter-compartmental clearance (Q) was significantly higher with mutant VEGF-A rs1570360 (p < 0.0001), and lower in patients with mutant VEGF-A rs699947 (p < 0.0001). The binding QSS model also showed that mutant ICAM-1 rs1799969 was associated with a lower CL (p = 0.0177). Mutant VEGF-A rs699947 was associated with a lower free VEGF-A levels, prior to the next dose (p = 0.000445). The above results were confirmed by the PK/PD model. Findings of the present study indicated that variants of the genes regulating angiogenesis might affect PK and PD characteristics of bevacizumab, possibly influencing the clinical outcomes.

Die Häufigkeit von Anti-VEGF-A-Injektionen und Ödemrezidiven hängt vom Grad der begleitenden lokalen zellulären Entzündung ab

2017 ◽  
Vol 3 (2) ◽  
pp. 70-71
Author(s):  
Olaf Strauss
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Adhesion Molecule ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Intercellular Adhesion Molecule ◽  
Vascular Endothelial ◽  
Intercellular Adhesion Molecule 1 ◽  
Endothelial Growth Factor ◽  
Zentrale Netzhautdicke

Wir maßen die Konzentrationen von Zytokinen und Wachstums-/Entzündungsfaktoren im Kammerwasser von 46 Patienten mit retinalem Venenastverschluss (VAV) und Makulaödem (MÖ), die mit einer intravitrealen Ranibizumab-Injektion (IRI) behandelt wurden. Patienten mit rezidivierendem MÖ erhielten bei Bedarf eine weitere IRI. Die Anzahl der IRI-Behandlungen korrelierte signifikant mit dem Alter, dem Visus c.c. bei Studienbeginn, der zentralen Netzhautdicke bei Studienbeginn sowie den Konzentrationen von 5 Zytokinen/Faktoren im Kammerwasser bei Studienbeginn (löslicher VEGFR-1 (vascular endothelial growth factor receptor 1), PDGF-AA (platelet-derived growth factor-AA), lösliches ICAM-1 (intercellular adhesion molecule 1), IL-6 (Interleukin 6) und IL-8). Die multivariate lineare Regressionsanalyse mit schrittweiser Auswahl bestätigte, dass Alter, zentrale Netzhautdicke bei Studienbeginn und PDGF-AA-Wert bei Studienbeginn unabhängige Determinanten der Anzahl der IRI-Behandlungen waren. Diese Ergebnisse deuten darauf hin, dass Entzündungsfaktoren möglicherweise das erneute Auftreten von MÖ bei VAV-Patienten beeinflussen können und dass der PDGF-AA-Wert ein hilfreicher Indikator dafür sein könnte, wie viele IRI-Behandlungen für die Beherrschung des MÖ erforderlich sein werden.

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