1.
Koch, Sina, et al.
(author)
Signal transduction by vascular endothelial growth factor receptors
2012
In: Cold Spring Harbor Perspectives in Medicine. - : Cold Spring Harbor Laboratory. - 2157-1422. ; 2:7, s. a006502-
Journal article (peer-reviewed) 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.
2.
Li, Xiujuan, et al.
(author)
Suppressed Vascular Leakage and Myocardial Edema Improve Outcome From Myocardial Infarction
2020
In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 11
Journal article (peer-reviewed) abstract
Aim: The acute phase of myocardial infarction (MI) is accompanied by edema contributing to tissue damage and disease outcome. Here, we aimed to identify the mechanism whereby vascular endothelial growth factor (VEGF)-A induces myocardial edema in the acute phase of MI to eventually promote development of therapeutics to specifically suppress VEGFA-regulated vascular permeability while preserving collateral vessel formation.Methods and Results: VEGFA regulates vascular permeability and edema by activation of VEGF receptor-2 (VEGFR2), leading to induction of several signaling pathways including the cytoplasmic tyrosine kinase c-Src. The activated c-Src in turn phosphorylates vascular endothelial (VE)-cadherin, leading to dissociation of endothelial adherens junctions. A particular tyrosine at position 949 in mouse VEGFR2 has been shown to be required for activation of c-Src. Wild-type mice and mice with phenylalanine replacing tyrosine (Y) 949 in VEGFR2 (Vegfr2Y949F/Y949F) were challenged with MI through permanent ligation of the left anterior descending coronary artery. The infarct size was similar in wild-type and mutant mice, but left ventricular wall edema and fibrinogen deposition, indicative of vascular leakage, were reduced in the Vegfr2Y949F/Y949F strain. When challenged with large infarcts, the Vegfr2Y949F/Y949F mice survived significantly better than the wild-type strain. Moreover, neutrophil infiltration and levels of myeloperoxidase were low in the infarcted Vegfr2Y949F/Y949F hearts, correlating with improved survival. In vivo tyrosine phosphorylation of VE-cadherin at Y685, implicated in regulation of vascular permeability, was induced by circulating VEGFA in the wild-type but remained at baseline levels in the Vegfr2Y949F/Y949F hearts.Conclusion: Suppression of VEGFA/VEGFR2-regulated vascular permeability leads to diminished edema without affecting vascular density correlating with improved myocardial parameters and survival after MI.
3.
Bahram, Fuad, et al.
(author)
VEGF-mediated signal transduction in lymphatic endothelial cells
2010
In: Pathophysiology : the official journal of the International Society for Pathophysiology / ISP. - : Elsevier BV. - 0928-4680. ; 17:4, s. 253-261
Journal article (peer-reviewed) abstract
The VEGF family of angiogenic ligands consists of VEGFA, VEGFB, VEGFC, VEGFD and placenta growth factor, PlGF. These growth factors bind in an overlapping pattern to three receptor tyrosine kinases, denoted VEGFR1, VEGFR2 and VEGFR3. Originally, VEGFA (the prototype VEGF) was described as a master regulator of vascular endothelial cell biology in vitro and in vivo, transducing its effect through VEGFR2. VEGFA, VEGFB and PlGF bind to VEGFR1, which is a negative regulator of endothelial cell function at least during embryogenesis. VEGFC and VEGFD were identified as lymphatic endothelial factors, acting via VEGFR3. With time, the very clear distinction between the roles of the VEGF ligands in angiogenesis/lymphangiogenesis has given way for a more complex pattern. It seems that the biology of the different VEGFR2 and VEGFR3 ligands overlaps quite extensively and that both receptor types contribute to angiogenesis as well as lymphangiogenesis. This paradigm shift in our understanding is due to the access to more sophisticated reagents and techniques revealing dynamic and plastic expression of ligands and receptors in different physiological and pathological conditions. Moreover, knowledge on the important role of VEGF coreceptors, the neuropilins, in regulating the responsiveness to VEGF has changed our perception on the mechanism of VEGF signal transduction. This review will primarily focus on the properties of VEGR3, its signal transduction and the resulting biology.
4.
Berge, Tone, et al.
(author)
T cell specific adapter protein (TSAd) interacts with Tec kinase ITK to promote CXCL12 induced migration of human and murine T cells
2010
In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 5:3, s. e9761-
Journal article (peer-reviewed) abstract
BACKGROUND: The chemokine CXCL12/SDF-1alpha interacts with its G-protein coupled receptor CXCR4 to induce migration of lymphoid and endothelial cells. T cell specific adapter protein (TSAd) has been found to promote migration of Jurkat T cells through interaction with the G protein beta subunit. However, the molecular mechanisms for how TSAd influences cellular migration have not been characterized in detail. PRINCIPAL FINDINGS: We show that TSAd is required for tyrosine phosphorylation of the Lck substrate IL2-inducible T cell kinase (Itk). Presence of Itk Y511 was necessary to boost TSAd's effect on CXCL12 induced migration of Jurkat T cells. In addition, TSAd's ability to promote CXCL12-induced actin polymerization and migration of Jurkat T lymphocytes was dependent on the Itk-interaction site in the proline-rich region of TSAd. Furthermore, TSAd-deficient murine thymocytes failed to respond to CXCL12 with increased Itk phosphorylation, and displayed reduced actin polymerization and cell migration responses. CONCLUSION: We propose that TSAd, through its interaction with both Itk and Lck, primes Itk for Lck mediated phosphorylation and thereby regulates CXCL12 induced T cell migration and actin cytoskeleton rearrangements.
5.
Hagberg, Carolina E, et al.
(author)
Vascular endothelial growth factor B controls endothelial fatty acid uptake.
2010
In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 464:7290, s. 917-21
Journal article (peer-reviewed) abstract
The vascular endothelial growth factors (VEGFs) are major angiogenic regulators and are involved in several aspects of endothelial cell physiology. However, the detailed role of VEGF-B in blood vessel function has remained unclear. Here we show that VEGF-B has an unexpected role in endothelial targeting of lipids to peripheral tissues. Dietary lipids present in circulation have to be transported through the vascular endothelium to be metabolized by tissue cells, a mechanism that is poorly understood. Bioinformatic analysis showed that Vegfb was tightly co-expressed with nuclear-encoded mitochondrial genes across a large variety of physiological conditions in mice, pointing to a role for VEGF-B in metabolism. VEGF-B specifically controlled endothelial uptake of fatty acids via transcriptional regulation of vascular fatty acid transport proteins. As a consequence, Vegfb(-/-) mice showed less uptake and accumulation of lipids in muscle, heart and brown adipose tissue, and instead shunted lipids to white adipose tissue. This regulation was mediated by VEGF receptor 1 and neuropilin 1 expressed by the endothelium. The co-expression of VEGF-B and mitochondrial proteins introduces a novel regulatory mechanism, whereby endothelial lipid uptake and mitochondrial lipid use are tightly coordinated. The involvement of VEGF-B in lipid uptake may open up the possibility for novel strategies to modulate pathological lipid accumulation in diabetes, obesity and cardiovascular diseases.
6.
Schmidt, Linnéa, et al.
(author)
Case-specific potentiation of glioblastoma drugs by pterostilbene
2016
In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:45, s. 73200-73215
Journal article (peer-reviewed) abstract
Glioblastoma multiforme (GBM, astrocytoma grade IV) is the most common malignant primary brain tumor in adults. Addressing the shortage of effective treatment options for this cancer, we explored repurposing of existing drugs into combinations with potent activity against GBM cells. We report that the phytoalexin pterostilbene is a potentiator of two drugs with previously reported anti-GBM activity, the EGFR inhibitor gefitinib and the antidepressant sertraline. Combinations of either of these two compounds with pterostilbene suppress cell growth, viability, sphere formation and inhibit migration in tumor GBM cell (GC) cultures. The potentiating effect of pterostilbene was observed to a varying degree across a panel of 41 patient-derived GCs, and correlated in a case specific manner with the presence of missense mutation of EGFR and PIK3CA and a focal deletion of the chromosomal region 1p32. We identify pterostilbene-induced cell cycle arrest, synergistic inhibition of MAPK activity and induction of Thioredoxin interacting protein (TXNIP) as possible mechanisms behind pterostilbene's effect. Our results highlight a nontoxic stilbenoid compound as a modulator of anticancer drug response, and indicate that pterostilbene might be used to modulate two anticancer compounds in well-defined sets of GBM patients.
7.
8.
Boye, Kevin, et al.
(author)
Endothelial Unc5B controls blood-brain barrier integrity
2022
In: Nature Communications. - : Springer Nature. - 2041-1723. ; 13:1
Journal article (peer-reviewed) abstract
The authors show that Netrin-1-Unc5B signaling controls blood-brain barrier integrity by maintaining Wnt/b-catenin signaling and that delivery of antibodies blocking Netrin-1 binding to Unc5B causes transient and size-selective BBB breakdown. Blood-brain barrier (BBB) integrity is critical for proper function of the central nervous system (CNS). Here, we show that the endothelial Unc5B receptor controls BBB integrity by maintaining Wnt/beta-catenin signaling. Inducible endothelial-specific deletion of Unc5B in adult mice leads to BBB leak from brain capillaries that convert to a barrier-incompetent state with reduced Claudin-5 and increased PLVAP expression. Loss of Unc5B decreases BBB Wnt/beta-catenin signaling, and beta-catenin overexpression rescues Unc5B mutant BBB defects. Mechanistically, the Unc5B ligand Netrin-1 enhances Unc5B interaction with the Wnt co-receptor LRP6, induces its phosphorylation and activates Wnt/beta-catenin downstream signaling. Intravenous delivery of antibodies blocking Netrin-1 binding to Unc5B causes a transient BBB breakdown and disruption of Wnt signaling, followed by neurovascular barrier resealing. These data identify Netrin-1-Unc5B signaling as a ligand-receptor pathway that regulates BBB integrity, with implications for CNS diseases.
9.
Claesson-Welsh, Lena, et al.
(author)
Permeability of the Endothelial Barrier : Identifying and Reconciling Controversies
2021
In: Trends in Molecular Medicine. - : Elsevier. - 1471-4914 .- 1471-499X. ; 27:4, s. 314-331
Research review (peer-reviewed) abstract
Leakage from blood vessels into tissues is governed by mechanisms that control endothelial barrier function to maintain homeostasis. Dysregulated endothelial permeability contributes to many conditions and can influence disease morbidity and treatment. Diverse approaches used to study endothelial permeability have yielded a wealth of valuable insights. Yet, ongoing questions, technical challenges, and unresolved controversies relating to the mechanisms and relative contributions of barrier regulation, transendothelial sieving, and transport of fluid, solutes, and particulates complicate interpretations in the context of vascular physiology and pathophysiology. Here, we describe recent in vivo findings and other advances in understanding endothelial barrier function with the goal of identifying and reconciling controversies over cellular and molecular processes that regulate the vascular barrier in health and disease.
10.
Claesson-Welsh, Lena, et al.
(author)
Tyrosine-protein kinase Yes is essential in vascular barrier dynamics
2022
In: Nature Cardiovascular Research. - : Springer Nature. - 2731-0590. ; 1:12, s. 1136-1137
Journal article (other academic/artistic) abstract
Endothelial cell-cell contacts in blood vessels constitute a barrier to the flux of molecules and cells from blood to tissues. We identified the tyrosine-protein kinase Yes as the principal regulator of collective endothelial cell migration and vascular barrier dynamics, a finding that opens avenues for future therapeutic development.
