VEGF receptor 2 (KDR) protects airways from mucus metaplasia through a Sox9-dependent pathway

2021 ◽  
Author(s):  
Ming Jiang ◽  
Yinshan Fang ◽  
Yu Li ◽  
Huachao Huang ◽  
Zichen Wei ◽  
...  
Keyword(s):  
Vegf Receptor ◽  
Dependent Pathway ◽  
Mucus Metaplasia

GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3474-3479 ◽  
Author(s):  
Klaus Podar ◽  
Laurence P. Catley ◽  
Yu-Tzu Tai ◽  
Reshma Shringarpure ◽  
Pedro Carvalho ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Bone Marrow Microenvironment ◽  
Vegf Receptor ◽  
Vegf Receptors ◽  
And Migration ◽  
Dependent Pathway

Abstract Previous studies have shown that the multiple myeloma (MM) cell line and MM patient cells express high-affinity vascular endothelial growth factor (VEGF) receptor-1 or Fms-like tyrosine kinase-1 (Flt-1) but not VEGF receptor-2 or Flk-1/kinase insert domain-containing receptor (Flk-1/KDR) and that VEGF triggers MM cell proliferation through a mitogen-activated protein kinase (MAPK)-dependent pathway and migration through a protein kinase C (PKC)-dependent pathway. The present study evaluates the efficacy of the small molecule tyrosine-kinase inhibitor GW654652, which inhibits all 3 VEGF receptors with similar potency. We show that GW654652 acts directly on MM cells and in the bone marrow microenvironment. Specifically, GW654652 (1-10 μg/mL) inhibits, in a dose-dependent fashion, VEGF-triggered migrational activity and cell proliferation of MM cell lines that are sensitive and resistant to conventional therapy. As expected from our previous studies of VEGF-induced signaling and sequelae in MM cells, GW654652 blocked VEGF-induced Flt-1 phosphorylation and downstream activation of AKT-1 and MAPK-signaling cascades. Importantly, GW654652 also inhibits interleukin-6 and VEGF secretion and proliferation of MM cells induced by tumor cell binding to bone marrow (BM) stromal cells. The activity of a pan-VEGF receptor inhibitor against MM cells in the BM milieu, coupled with its lack of major toxicity in preclinical mouse models, provides the framework for clinical trials of this drug class to improve patient outcome in MM. (Blood. 2004;103:3474-3479)

Abstract 648: Alternative Macrophages Promote Atherosclerosis Progression by Increasing Intraplaque Angiogenesis and Vascular Permeability via HIF-1 alpha/VEGF-A-dependent Pathway

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Liang Guo ◽  
Hirokuni Akahori ◽  
Rohini Polavarapu ◽  
Emannuel Harari ◽  
Vinit Karmali ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Cultured Cells ◽  
Foam Cell ◽  
Macrophage Polarization ◽  
Intraplaque Hemorrhage ◽  
Cell Phenotype ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Dependent Pathway

Background: Alternative macrophages exist in human atherosclerosis but their role in atherogenesis remains uncertain. Intraplaque hemorrhage (IPH) is an important stimulus driving alternative macrophage polarization. Intake of hemoglobin (Hb) by the hemoglobin: haptoglobin receptor CD163 leads to a distinct non-foam cell phenotype termed M(Hb). These cells demonstrate upregulation of CD163, lack of lipid retention, and anti-oxidative properties, characteristics considered ‘atheroprotective’. Here we reveal an unexpected but important pathogenic role for M(Hb) in atherosclerosis. Objectives: To determine the role of M(Hb) macrophages in human intraplaque angiogenesis and vascular permeability. Methods: Using human atherosclerotic samples, cultured cells, and a mouse model of IPH, we investigated the role of IPH on macrophage function with respect to angiogenesis and vascular permeability. Results: Within M(Hb) activation of hypoxia-inducible factor-1 alpha (HIF-1) via inhibition of prolyl hydroxylases promotes intraplaque angiogenesis and vascular permeability. In human carotid plaques, alternative CD163 positive macrophages were found to be highly associated with plaque vascularity and expressed high levels of HIF1- and vascular endothelial growth factor-A (VEGF-A). Supernatants from hemoglobin:haptoglobin differentiated M(Hb) macrophages increased endothelial permeability and led to internalization of the endothelial barrier protein vascular endothelial cadherin (VE-cadherin) via activation of VEGF receptor 2 (VEGFR2). Areas of plaque demonstrating high density CD163 high macrophage subsets showed irregular VE-cadherin immunostaining and diffuse perivascular collections of von Willebrand factor suggesting microvessel incompetence. Finally, in brachiocephalic plaques of one-year-old apoE -/- and apoE -/- CD163 -/- mice, CD163 deficiency significantly reduced plaque progression, lesion size, and intraplaque hemorrhage, but had little effect on lesions uncomplicated by hemorrhage. Conclusions: Our findings provide a novel non-lipid driven mechanism by which alterative M(Hb) macrophages promote plaque neoangiogenesis and microvessel incompetence via a HIF-1/VEGF-A-dependent pathway.

The Mechanism of Platelet Aggregation Induced by HLA-Related Antibodies

1996 ◽  
Vol 76 (05) ◽  
pp. 774-779 ◽  
Author(s):  
John T Brandt ◽  
Carmen J Julius ◽  
Jeanne M Osborne ◽  
Clark L Anderson
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Complement Activation ◽  
Thromboembolic Disease ◽  
Clinical Samples ◽  
Hla Antigen ◽  
Aggregation Response ◽  
Immune Mediated ◽  
Dependent Pathway

SummaryImmune-mediated platelet activation is emerging as an important pathogenic mechanism of thrombosis. In vitro studies have suggested two distinct pathways for immune-mediated platelet activation; one involving clustering of platelet FcyRIIa, the other involving platelet-associated complement activation. HLA-related antibodies have been shown to cause platelet aggregation, but the mechanism has not been clarified. We evaluated the mechanism of platelet aggregation induced by HLA-related antibodies from nine patients. Antibody to platelet FcyRIIa failed to block platelet aggregation with 8/9 samples, indicating that engagement of platelet FcyRIIa is not necessary for the platelet aggregation induced by HLA-related antibodies. In contrast, platelet aggregation was blocked by antibodies to human C8 (5/7) or C9 (7/7). F(ab’)2 fragments of patient IgG failed to induce platelet activation although they bound to HLA antigen on platelets. Intact patient IgG failed to aggregate washed platelets unless aged serum was added. The activating IgG could be adsorbed by incubation with lymphocytes and eluted from the lymphocytes. These results indicate that complement activation is involved in the aggregation response to HLA-related antibodies. This is the first demonstration of complement-mediated platelet aggregation by clinical samples. Five of the patients developed thrombocytopenia in relationship to blood transfusion and two patients developed acute thromboembolic disease, suggesting that these antibodies and the complement-dependent pathway of platelet aggregation may be of clinical significance.

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