SwePub - search: WFRF:(Claesson Welsh Lena)

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1.	Claesson-Welsh, Lena, et al. (author) Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD 1998 In: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424 .- 1091-6490. ; 95:10, s. 5579-5583 Journal article (peer-reviewed)abstract Angiostatin, a fragment of plasminogen, has been identified and characterized as an endogenous inhibitor of neovascularization. We show that angiostatin treatment of endothelial cells in the absence of growth factors results in an increased apoptotic index whereas the proliferation index is unchanged. Angiostatin also inhibits migration and tube formation of endothelial cells. Angiostatin treatment has no effect on growth factor-induced signal transduction but leads to an RGD-independent induction of the kinase activity of focal adhesion kinase, suggesting that the biological effects of angiostatin relate to subversion of adhesion plaque formation in endothelial cells.
2.	Claesson-Welsh, Lena, et al. (author) VEGFA and tumour angiogenesis 2013 In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 273:2, s. 114-127 Research review (peer-reviewed)abstract In this review we summarize the current understanding of signal transduction downstream of vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2, and the relationship between these signal transduction pathways and the hallmark responses of VEGFA, angiogenesis and vascular permeability. These physiological responses involve a number of effectors, including extracellular signal-regulated kinases (ERKs), Src, phosphoinositide 3 kinase (PI3K)/Akt, focal adhesion kinase (FAK), Rho family GTPases, endothelial NO and p38 mitogen-activated protein kinase (MAPK). Several of these factors are involved in the regulation of both angiogenesis and vascular permeability. Tumour angiogenesis primarily relies on VEGFA-driven responses, which to a large extent result in a dysfunctional vasculature. The reason for this remains unclear, although it appears that certain aspects of the VEGFA-stimulated angiogenic milieu (high level of microvascular density and permeability) promote tumour expansion. The high degree of redundancy and complexity of VEGFA-driven tumour angiogenesis may explain why tumours commonly develop resistance to anti-angiogenic therapy targeting VEGFA signal transduction.
3.	Cross, Michael J, et al. (author) The Shb Adaptor Protein Binds to Tyrosine 766 in the FGFR-1 and Regulatesthe Ras/MEK/MAPK Pathway via FRS2 Phosphorylation in Endothelial Cells 2002 In: Molecular Biology of the Cell. - 1059-1524 .- 1939-4586. ; 13:8, s. 2881-2893 Journal article (peer-reviewed)abstract Stimulation of fibroblast growth factor receptor-1 (FGFR-1) is known to result in phosphorylation of tyrosine 766 and the recruitment and subsequent activation of phospholipase C-γ (PLC-γ). To assess the role of tyrosine 766 in endothelial cell function, we generated endothelial cells expressing a chimeric receptor, composed of the extracellular domain of the PDGF receptor-α and the intracellular domain of FGFR-1. Mutation of tyrosine 766 to phenylalanine prevented PLC-γ activation and resulted in a reduced phosphorylation of FRS2 and reduced activation of the Ras/MEK/MAPK pathway relative to the wild-type chimeric receptor. However, FGFR-1–mediated MAPK activation was not dependent on PKC activation or intracellular calcium, both downstream mediators of PLC-γ activation. We report that the adaptor protein Shb is also able to bind tyrosine 766 in the FGFR-1, via its SH2 domain, resulting in its subsequent phosphorylation. Overexpression of an SH2 domain mutant Shb caused a dramatic reduction in FGFR-1–mediated FRS2 phosphorylation with concomitant perturbment of the Ras/MEK/MAPK pathway. Expression of the chimeric receptor mutant and the Shb SH2 domain mutant resulted in a similar reduction in FGFR-1–mediated mitogenicity. We conclude, that Shb binds to tyrosine 766 in the FGFR-1 and regulates FGF-mediated mitogenicity via FRS2 phosphorylation and the subsequent activation of the Ras/MEK/MAPK pathway.
4.	Dixelius, Johan, et al. (author) Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis 2000 In: Blood. - 0006-4971 .- 1528-0020. ; 95:11, s. 3403-3411 Journal article (peer-reviewed)abstract Endostatin, which corresponds to the C-terminal fragment of collagen XVIII, is a potent inhibitor of angiogenesis. Fibroblast growth factor-2 (FGF-2)-induced angiogenesis in the chicken chorioallantoic membrane was inhibited by endostatin, but not by an endostatin mutant R158/270A, lacking heparin-binding ability. Endostatin was internalized by endothelial cells, but not by mouse fibroblasts. Treatment of murine brain endothelial (IBE) cells with endostatin reduced the proportion of cells in S phase, whereas growth-arrested IBE cells in collagen gels treated with endostatin displayed enhanced tubular morphogenesis. IBE cells overexpressing Shb, an adaptor protein implicated in angiostatin-induced apoptosis, displayed elevated apoptosis and decreased tubular morphogenesis in collagen gels in response to endostatin when added together with FGF-2. Induction of apoptosis was dependent on the heparin-binding ability of endostatin and the expression of Shb with a functional Src homology 2 (SH2)-domain. Endostatin treatment for 10 minutes or 24 hours induced tyrosine phosphorylation of Shb and formation of multiprotein complexes. An Shb SH2 domain fusion protein precipitated a 125-kd phosphotyrosyl protein in endostatin-treated cells. The 125-kd component either contained intrinsic tyrosine kinase activity or occurred in complex with a tyrosine kinase. In conclusion, our data show that endostatin induces tyrosine kinase activity and enhanced apoptosis in FGF-treated endothelial cells.
5.	Holmqvist, Kristina, et al. (author) The adaptor protein Shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration. 2004 In: J Biological chemistry. ; 279:21, s. 22267-22275 Journal article (peer-reviewed)
6.	Hooshmand-Rad, Roya, et al. (author) Platelet-Derived Growth Factor-Mediated Signaling through the Shb Adaptor Protein : Effects on Cytoskeletal Organization 2000 In: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 257:2, s. 245-254 Journal article (peer-reviewed)abstract The Src homology (SH) 2 domain adaptor protein Shb has previously been shown to interact with the platelet-derived growth factor (PDGF)-β receptor. In this study we show an association between Shb and the PDGF-α receptor which is mediated by the SH2 domain of Shb and involves tyrosine residue 720 in the kinase insert domain of the receptor. To assess the role of Shb in PDGF-mediated signaling, we have overexpressed wild-type Shb or Shb carrying a mutation (R522K) which renders the SH2 domain inactive, in Patch mouse (PhB) fibroblasts expressing both PDGF receptors (PhB/Rα). Overexpression of wild-type Shb, but not the R522K Shb mutant, affected PDGF-mediated reorganization of the cytoskeleton by decreasing membrane ruffle formation and stimulating the generation of filopodia relative the parental control cells. In addition, the PDGF-induced receptor-associated phosphatidylinositol 3′-kinase activity and phosphorylation of Akt was similar in both PhB/Rα/Shb and PhB/Rα/ShbR522K cells compared with the parental control, whereas the activation of Rac in response to PDGF-BB was diminished only in the PhB/Rα/Shb cells. We conclude that Shb plays a role in PDGF-dependent regulation of certain cytoskeletal changes by modulating the ability of PDGF to activate Rac.
7.	Jakobsson, Lars, et al. (author) Heparan sulfate in trans potentiates VEGFR-mediated angiogenesis 2006 In: Developmental Cell. - 1534-5807 .- 1878-1551. ; 10:5, s. 625-634 Journal article (peer-reviewed)abstract Several receptor tyrosine kinases require heparan sulfate proteoglycans (HSPGs) as coreceptors for efficient signal transduction. We have studied the role of HSPGs in the development of blood capillary structures from embryonic stem cells, a process strictly dependent on signaling via vascular endothelial growth factor receptor-2 (VEGFR-2). We show, by using chimeric cultures of embryonic stem cells defective in either HS production or VEGFR-2 synthesis, that VEGF signaling in endothelial cells is fully supported by HS expressed in trans by adjacent perivascular smooth muscle cells. Transactivation of VEGFR-2 leads to prolonged and enhanced signal transduction due to HS-dependent trapping of the active VEGFR-2 signaling complex. Our data imply that direct signaling via HSPG core proteins is dispensable for a functional VEGF response in endothelial cells. We propose that transactivation of tyrosine kinase receptors by HSPGs constitutes a mechanism for crosstalk between adjacent cells.
8.	Jin, Yi, et al. (author) Tyrosine-protein kinase Yes controls endothelial junctional plasticity and barrier integrity by regulating VE-cadherin phosphorylation and endocytosis 2022 In: Nature Cardiovascular Research. - : Springer Nature. - 2731-0590. ; 1:12, s. 1156-1173 Journal article (peer-reviewed)abstract Vascular endothelial (VE)-cadherin in endothelial adherens junctions is an essential component of the vascular barrier, critical for tissue homeostasis and implicated in diseases such as cancer and retinopathies. Inhibitors of Src cytoplasmic tyrosine kinase have been applied to suppress VE-cadherin tyrosine phosphorylation and prevent excessive leakage, edema and high interstitial pressure. Here we show that the Src-related Yes tyrosine kinase, rather than Src, is localized at endothelial cell (EC) junctions where it becomes activated in a flow-dependent manner. EC-specific Yes1 deletion suppresses VE-cadherin phosphorylation and arrests VE-cadherin at EC junctions. This is accompanied by loss of EC collective migration and exaggerated agonist-induced macromolecular leakage. Overexpression of Yes1 causes ectopic VE-cadherin phosphorylation, while vascular leakage is unaffected. In contrast, in EC-specific Src deficiency, VE-cadherin internalization is maintained and leakage is suppressed. In conclusion, Yes-mediated phosphorylation regulates constitutive VE-cadherin turnover, thereby maintaining endothelial junction plasticity and vascular integrity.
9.	Karlsson, Torbjörn, et al. (author) Molecular interactions of the Src homology 2 domain protein Shb with phosphotyrosine residues, tyrosine kinase receptors and Src homology 3 domain proteins 1995 In: Oncogene. - 0950-9232 .- 1476-5594. ; 10:8, s. 1475-1483 Journal article (peer-reviewed)abstract The molecular interactions of the Src homology 2 (SH2) domain and the N-terminal proline-rich sequence motifs (pro-1 to pro-5) of the SH2 protein Shb with other components were presently characterised. Using a degenerate phosphopeptide library the preferred binding site for the Shb SH2 domain was determined to pTyr-Thr/Val/Ile-X-Leu at positions +1 to +3 relative the phosphotyrosine residue. Experiments with competing peptides and platelet-derived growth factor (PDGF) beta-receptor mutants with Y to F substitutions in autophosphorylation sites revealed multiple binding sites for the Shb SH2 domain in the receptor. The Shb SH2 domain also binds to in vitro phosphorylated fibroblast growth factor receptor-1 (FGFR-1) mainly through position Y776. The receptor experiments suggest that other residues besides the +1 to +3 positions may also be of significance for Shb binding. The pro-4/pro-5 motif of Shb binds in vitro particularly well to the Src, p85 alpha PI3-kinase and Eps8 SH3 domains expressed as GST fusion proteins. However, the GST-SH3 domain fusion proteins tested bind in vitro to peptides corresponding to the pro-1 to pro-5 motifs of Shb with low affinity and selectivity, suggesting that sequences outside the core proline motif may also be important for Shb-SH3 domain interactions. In vivo association between Shb-SH3 domain proteins v-Src and Eps8 was detected by coimmunoprecipitation. PDGF treatment did not affect the association between Eps8 and Shb. The data suggest that Shb is an adaptor protein linking SH3 domain proteins to tyrosine kinases or other tyrosine phosphorylated proteins.
10.	Kawamura, Harukiyo, et al. (author) Neuropilin-1 in regulation of VEGF-induced activation of p38MAPK and endothelial cell organization 2008 In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 112:9, s. 3638-49 Journal article (peer-reviewed)abstract Vascular endothelial growth factor (VEGF)-A regulates vascular development and angiogenesis. VEGF isoforms differ in ability to bind coreceptors heparan sulfate (HS) and neuropilin-1 (NRP1). We used VEGF-A165 (which binds HS and NRP1), VEGF-A121 (binds neither HS nor NRP1), and parapoxvirus VEGF-E-NZ2 (binds NRP1 but not HS) to investigate the role of NRP1 in organization of endothelial cells into vascular structures. All 3 ligands induced similar level of VEGFR-2 tyrosine phosphorylation in the presence of NRP1. In contrast, sprouting angiogenesis in differentiating embryonic stem cells (embryoid bodies), formation of branching pericyte-embedded vessels in subcutaneous matrigel plugs, and sprouting of intersegmental vessels in developing zebrafish were induced by VEGF-A165 and VEGF-E-NZ2 but not by VEGF-A121. Analyses of recombinant factors with NRP1-binding gain- and loss-of-function properties supported the conclusion that NRP1 is critical for VEGF-induced sprouting and branching of endothelial cells. Signal transduction antibody arrays implicated NRP1 in VEGF-induced activation of p38MAPK. Inclusion of the p38MAPK inhibitor SB203580 in VEGF-A165-containing matrigel plugs led to attenuated angiogenesis and poor association with pericytes. Our data strongly indicate that the ability of VEGF ligands to bind NRP1 influences p38MAPK activation, and formation of functional, pericyte-associated vessels.
11.	Le Jan, Sébastien, et al. (author) Functional Overlap Between Chondroitin and Heparan Sulfate Proteoglycans During VEGF-Induced Sprouting Angiogenesis 2012 In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 32:5, s. 1255-1263 Journal article (peer-reviewed)abstract OBJECTIVE: Heparan sulfate proteoglycans regulate key steps of blood vessel formation. The present study was undertaken to investigate if there is a functional overlap between heparan sulfate proteoglycans and chondroitin sulfate proteoglycans during sprouting angiogenesis.METHODS AND RESULTS: Using cultures of genetically engineered mouse embryonic stem cells, we show that angiogenic sprouting occurs also in the absence of heparan sulfate biosynthesis. Cells unable to produce heparan sulfate instead increase their production of chondroitin sulfate that binds key angiogenic growth factors such as vascular endothelial growth factor A, TGFβ, and platelet-derived growth factor B. Lack of heparan sulfate proteoglycan production however leads to increased pericyte numbers and reduced adhesion of pericytes to nascent sprouts, likely due to dysregulation of TGFβ and platelet-derived growth factor B signal transduction.CONCLUSIONS: The present study provides direct evidence for a previously undefined functional overlap between chondroitin sulfate proteoglycans and heparan sulfate proteoglycans during sprouting angiogenesis. Our findings provide information relevant for potential future drug design efforts that involve targeting of proteoglycans in the vasculature.
12.	Massena, Sara, et al. (author) Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans 2015 In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 126:17, s. 2016-2026 Journal article (peer-reviewed)abstract Vascular endothelial growth factor A (VEGF-A) is upregulated during hypoxia and is the major regulator of angiogenesis. VEGF-A expression has also been found to recruit myeloid cells to ischemic tissues where they contribute to angiogenesis. This study investigates the mechanisms underlying neutrophil recruitment to VEGF-A as well as the characteristics of these neutrophils. A previously undefined circulating subset of neutrophils shown to be CD49d(+)VEGFR1(high)CXCR4(high) was identified in mice and humans. By using chimeric mice with impaired VEGF receptor 1 (VEGFR1) or VEGFR2 signaling (Flt-1tk(-/-), tsad(-/-)), we found that parallel activation of VEGFR1 on neutrophils and VEGFR2 on endothelial cells was required for VEGF-A-induced recruitment of circulating neutrophils to tissue. Intravital microscopy of mouse microcirculation revealed that neutrophil recruitment by VEGF-A versus by the chemokine macrophage inflammatory protein 2 (MIP-2 [CXCL2]) involved the same steps of the recruitment cascade but that an additional neutrophil integrin (eg, VLA-4 [CD49d/CD29]) played a crucial role in neutrophil crawling and emigration to VEGF-A. Isolated CD49d(+) neutrophils featured increased chemokinesis but not chemotaxis compared with CD49d(-) neutrophils in the presence of VEGF-A. Finally, by targeting the integrin α4 subunit (CD49d) in a transplantation-based angiogenesis model that used avascular pancreatic islets transplanted to striated muscle, we demonstrated that inhibiting the recruitment of circulating proangiogenic neutrophils to hypoxic tissue impairs vessel neoformation. Thus, angiogenesis can be modulated by targeting cell-surface receptors specifically involved in VEGF-A-dependent recruitment of proangiogenic neutrophils without compromising recruitment of the neutrophil population involved in the immune response to pathogens.
13.	Massena, Sara, et al. (author) The mechanisms of VEGF-A-induced recruitment of pro-angiogenic neutrophils 2013 In: European Journal of Clinical Investigation. - 0014-2972 .- 1365-2362. ; 43:SI, s. 27-27 Journal article (other academic/artistic)
14.	Pietilä, Ilkka, et al. (author) Temporal Dynamics of VEGFA-Induced VEGFR2/FAK Co-Localization Depend on SHB 2019 In: Cells. - Basel, Switzerland : MDPI. - 2073-4409. ; 8:12 Journal article (peer-reviewed)abstract Focal adhesion kinase (FAK) is essential for vascular endothelial growth factor-A (VEGFA)/VEGF receptor-2 (VEGFR2)-stimulated angiogenesis and vascular permeability. We have previously noted that presence of the Src homology-2 domain adapter protein B (SHB) is of relevance for VEGFA-stimulated angiogenesis in a FAK-dependent manner. The current study was conducted in order address the temporal dynamics of co-localization between these components in HEK293 and primary lung endothelial cells (EC) by total internal reflection fluorescence microscopy (TIRF). An early (<2.5 min) VEGFA-induced increase in VEGFR2 co-localization with SHB was dependent on tyrosine 1175 in VEGFR2. VEGFA also enhanced SHB co-localization with FAK. FAK co-localization with VEGFR2 was dependent on SHB since it was significantly lower in SHB deficient EC after VEGFA addition. Absence of SHB also resulted in a gradual decline of VEGFR2 co-localization with FAK under basal (prior to VEGFA addition) conditions. A similar basal response was observed with expression of the Y1175F-VEGFR2 mutant in wild type EC. The distribution of focal adhesions in SHB-deficient EC was altered with a primarily perinuclear location. These live cell data implicate SHB as a key component regulating FAK activity in response to VEGFA/VEGFR2.
15.	Roche, Francis P., et al. (author) Leukocyte differentiation by histidine-rich glycoprotein/stanniocalcin-2 complex regulates murine glioma growth through modulation of anti-tumor immunity 2018 In: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 17:9, s. 1961-1972 Journal article (peer-reviewed)abstract The plasma-protein histidine-rich glycoprotein (HRG) is implicated in phenotypic switching of tumor-associated macrophages, regulating cytokine production and phagocytotic activity, thereby promoting vessel normalization and anti-tumor immune responses. To assess the therapeutic effect of HRG gene delivery on CNS tumors, we used adenovirus-encoded HRG to treat mouse intracranial GL261 glioma. Delivery of Ad5-HRG to the tumor site resulted in a significant reduction in glioma growth, associated with increased vessel perfusion and increased CD45+ leukocyte and CD8+ T cell accumulation in the tumor. Antibody-mediated neutralization of colony-stimulating factor-1 suppressed the effects of HRG on CD45+ and CD8+ infiltration. Using a novel protein interaction-decoding technology, TRICEPS-based ligand receptor capture (LRC), we identified Stanniocalcin-2 (STC2) as an interacting partner of HRG on the surface of inflammatory cells in vitro and co-localization of HRG and STC2 in gliomas. HRG reduced the suppressive effects of STC2 on monocyte CD14+ differentiation and STC2-regulated immune response pathways. In consequence, Ad5-HRG treated gliomas displayed decreased numbers of Interleukin-35+ Treg cells, providing a mechanistic rationale for the reduction in GL261 growth in response to Ad5-HRG delivery. We conclude that HRG suppresses glioma growth by modulating tumor inflammation through monocyte infiltration and differentiation. Moreover, HRG acts to balance the regulatory effects of its partner, STC2, on inflammation and innate and/or acquired immunity. HRG gene delivery therefore offers a potential therapeutic strategy to control anti-tumor immunity.
16.	Rolny, Charlotte, et al. (author) Platelet-derived growth factor receptor-beta promotes early endothelial cell differentiation 2006 In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 108:6, s. 1877-1886 Journal article (peer-reviewed)abstract Platelet-derived growth factor BB (PDGF-BB) has been assigned a critical role in vascular stability by promoting the recruitment of PDGF receptor-beta-expressing perivascular cells. Here we present data indicating that early hematopoietic/endothelial (hemangio) precursors express PDGFR-beta based on coexpression with CD31, vascular endothelial growth factor receptor-2, and CD41 in 2 models: mouse yolk sac (embryonic day 8 [E8]) and differentiating mouse embryonic stem cells (embryoid bodies). Expression of PDGFR-beta on hemangioprecursor cells in the embryoid bodies gradually disappeared, and, at E14, expression appeared on perivascular cells. Activation of the PDGFR-beta on the hemangioprecursors accelerated the differentiation of endothelial cells, whereas differentiation of the hematopoietic lineage was suppressed. In E9.5 yolk sacs derived from recombinant mice expressing kinase-active PDGFR-beta with an aspartic acid to asparagine (D894N) replacement in the kinase activating loop and from mice with ubiquitous expression of PDGF-BB driven by the Rosa26 locus, the number of CD41-expressing early hematopoietic cells decreased by 36% and 34%, respectively, compared with staged wild-type littermates. Moreover, enhanced vascular remodeling was evident in the Rosa26-PDGF-BB yolk sacs. We conclude that PDGFR-beta is expressed on early hemangioprecursor cells, regulating vascular/hematopoietic development.
17.	Aase, Karin, et al. (author) Angiomotin regulates endothelial cell migration during embryonic angiogenesis 2007 In: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 21:16, s. 2055-2068 Journal article (peer-reviewed)abstract The development of the embryonic vascular system into a highly ordered network requires precise control over the migration and branching of endothelial cells (ECs). We have previously identified angiomotin (Amot) as a receptor for the angiogenesis inhibitor angiostatin. Furthermore, DNA vaccination targeting Amot inhibits angiogenesis and tumor growth. However, little is known regarding the role of Amot in physiological angiogenesis. We therefore investigated the role of Amot in embryonic neovascularization during zebrafish and mouse embryogenesis. Here we report that knockdown of Amot in zebrafish reduced the number of filopodia of endothelial tip cells and severely impaired the migration of intersegmental vessels. We further show that 75% of Amot knockout mice die between embryonic day 11 (E11) and E11.5 and exhibit severe vascular insufficiency in the intersomitic region as well as dilated vessels in the brain. Furthermore, using ECs differentiated from embryonic stem (ES) cells, we demonstrate that Amot-deficient cells have intact response to vascular endothelial growth factor (VEGF) in regard to differentiation and proliferation. However, the chemotactic response to VEGF was abolished in Amot-deficient cells. We provide evidence that Amot is important for endothelial polarization during migration and that Amot controls Rac1 activity in endothelial and epithelial cells. Our data demonstrate a critical role for Amot during vascular patterning and endothelial polarization.
18.	Arbiser, Jack L., et al. (author) Functional tyrosine kinase inhibitor profiling : a generally applicable method points to a novel role of platelet-derived growth factor receptor-beta in tuberous sclerosis 2002 In: American Journal of Pathology. - 0002-9440 .- 1525-2191. ; 161:3, s. 781-786 Journal article (peer-reviewed)abstract Tumors often exhibit activation of specific tyrosine kinases, which may allow targeting of therapy through inhibition of tyrosine kinase signaling. This strategy has been used successfully in the development of STI571 (gleevec), an inhibitor of bcr-abl tyrosine kinase that has been used successfully in the treatment of chronic myelogenous leukemia. STI571 also shows activity against c-kit and platelet-derived growth factor receptor-beta (PDGFRbeta) tyrosine kinase signaling, thus potentially expanding the number of tumors that may respond to it. We describe a simple and rapid method to assess functional activity of tyrosine kinase signaling that is broadly applicable to tumor types. As proof of principle, we have applied it to cells that serve as models of the autosomal-dominant tumor syndrome tuberous sclerosis (TS). We found that TS model cells derived from tuberin heterozygous mice and from a human renal angiomyolipoma are highly sensitive to PDGFR antagonists and that these cells express PDGFRbeta. Given that PDGFRbeta signaling is inhibited by STI571, we found that SV7tert human angiomyolipoma cells are sensitive to STI571. Thus, we describe a novel but simple method of determining the functional tyrosine kinase profile of a neoplastic cell and our results suggest that STI571 might be useful in the treatment of neoplasms commonly seen in patients with TS.
19.	Arbiser, JL, et al. (author) Overexpression of VEGF 121 in inmortalized endothelial cells causes conversion to slowly growing angiosarcoma and high level expression of the VEGF receptors VEGFR-1 and VEGFR-2 in vivo. 2000 In: Am. J. Pathol.. ; 156, s. 1469- Journal article (peer-reviewed)
20.	Arvidsson, Ann-Kristin, et al. (author) Tyr-716 in the platelet-derived growth factor beta-receptor kinase insertis involved in GRB2 binding and Ras activation 1994 In: Molecular and Cellular Biology. - : American Society for Microbiology. - 0270-7306 .- 1098-5549. ; 14:10, s. 6715-6726 Journal article (peer-reviewed)abstract Ligand stimulation of the platelet-derived growth factor (PDGF) beta-receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation of the intracellular part of the receptor. The autophosphorylated tyrosine residues mediate interactions with downstream signal transduction molecules and thereby initiate different signalling pathways. A pathway leading to activation of the GTP-binding protein Ras involves the adaptor molecule GRB2. Here we show that Tyr-716, a novel autophosphorylation site in the PDGF beta-receptor kinase insert, mediates direct binding of GRB2 in vitro and in vivo. In a panel of mutant PDGF beta-receptors, in which Tyr-716 and the previously known autophosphorylation sites were individually mutated, only PDGFR beta Y716F failed to bind GRB2. Furthermore, a synthetic phosphorylated peptide containing Tyr-716 bound GRB2, and this peptide specifically interrupted the interaction between GRB2 and the wild-type receptor. In addition, the Y716(P) peptide significantly decreased the amount of GTP bound to Ras in response to PDGF in permeabilized fibroblasts as well as in porcine aortic endothelial cells expressing transfected PDGF beta-receptors. The mutant PDGFR beta Y716F still mediated activation of mitogen-activated protein kinases and an increased DNA synthesis in response to PDGF, indicating that multiple signal transduction pathways transduce mitogenic signals from the activated PDGF beta-receptor.
21.	Ashrafzadeh, Parham, et al. (author) Exocyst complex component 7 (EXOC7) regulates vascular endothelial growth factor receptor 2 (VEGFR2) trafficking to the plasma membrane Other publication (other academic/artistic)
22.	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.
23.	Bentley, Katie, et al. (author) The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis 2014 In: Nature Cell Biology. - : Springer Science and Business Media LLC. - 1465-7392 .- 1476-4679. ; 16:4, s. 309-321 Journal article (peer-reviewed)abstract Endothelial cells show surprising cell rearrangement behaviour during angiogenic sprouting; however, the underlying mechanisms and functional importance remain unclear. By combining computational modelling with experimentation, we identify that Notch/VEGFR-regulated differential dynamics of VE-cadherin junctions drive functional endothelial cell rearrangements during sprouting. We propose that continual flux in Notch signalling levels in individual cells results in differential VE-cadherin turnover and junctional-cortex protrusions, which powers differential cell movement. In cultured endothelial cells, Notch signalling quantitatively reduced junctional VE-cadherin mobility. In simulations, only differential adhesion dynamics generated long-range position changes, required for tip cell competition and stalk cell intercalation. Simulation and quantitative image analysis on VE-cadherin junctional patterning in vivo identified that differential VE-cadherin mobility is lost under pathological high VEGF conditions, in retinopathy and tumour vessels. Our results provide a mechanistic concept for how cells rearrange during normal sprouting and how rearrangement switches to generate abnormal vessels in pathologies.
24.	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.
25.	Bhattacharya, Resham, et al. (author) Distinct role of PLC{beta}3 in VEGF-mediated directional migration and vascular sprouting 2009 In: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 122:7, s. 1025-1034 Journal article (peer-reviewed)abstract Endothelial cell proliferation and migration is essential to angiogenesis. Typically, proliferation and chemotaxis of endothelial cells is driven by growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). VEGF activates phospholipases (PLCs) - specifically PLCgamma1 - that are important for tubulogenesis, differentiation and DNA synthesis. However, we show here that VEGF, specifically through VEGFR2, induces phosphorylation of two serine residues on PLCbeta3, and this was confirmed in an ex vivo embryoid body model. Knockdown of PLCbeta3 in HUVEC cells affects IP3 production, actin reorganization, migration and proliferation; whereas migration is inhibited, proliferation is enhanced. Our data suggest that enhanced proliferation is precipitated by an accelerated cell cycle, and decreased migration by an inability to activate CDC42. Given that PLCbeta3 is typically known as an effector of heterotrimeric G-proteins, our data demonstrate a unique crosstalk between the G-protein and receptor tyrosine kinase (RTK) axes and reveal a novel molecular mechanism of VEGF signaling and, thus, angiogenesis.
26.	Blume-Jensen, Peter, et al. (author) Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis 1991 In: EMBO Journal. - 0261-4189 .- 1460-2075. ; 10:13, s. 4121-4128 Journal article (peer-reviewed)abstract The proto-oncogene c-kit is allelic with the murine white spotting (W) locus and encodes a transmembrane protein tyrosine kinase that is structurally related to the receptors for platelet-derived growth factor (PDGF) and colony-stimulating factor-1 (CSF-1). Recently the ligand for the c-kit product, stem cell factor (SCF), was identified in both transmembrane and soluble forms. In order to examine the mechanism for receptor activation by SCF and biological properties of the activated c-kit product, we transfected the wild-type human c-kit cDNA into porcine aortic endothelial cells. We found that the receptor was down-regulated and transmitted a mitogenic signal in response to stimulation with soluble SCF. We also demonstrate that SCF induces dimerization of the c-kit product in intact cells, and that dimerization of the receptor is correlated with activation of its kinase. Activation of the c-kit product by SCF was found to induce circular actin reorganization indistinguishable from that mediated by the PDGF beta-receptor in response to PDGF-BB. Furthermore, soluble SCF was a potent chemotactic agent for cells expressing the c-kit product, a property which might be of importance during embryonic development.
27.	Bohman, Svante, et al. (author) Proteomic analysis of vascular endothelial growth factor-induced endothelial cell differentiation reveals a role for chloride intracellular channel 4 (CLIC4) in tubular morphogenesis. 2005 In: J Biol Chem. - 0021-9258. ; 280:51, s. 42397-404 Journal article (peer-reviewed)
28.	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.
29.	Caolo, Vincenza, et al. (author) Shear Stress and VE-Cadherin : The Molecular Mechanism of Vascular Fusion 2018 In: Arteriosclerosis, Thrombosis and Vascular Biology. - : LIPPINCOTT WILLIAMS & WILKINS. - 1079-5642 .- 1524-4636. ; 38:9, s. 2174-2183 Journal article (peer-reviewed)abstract Objective: Vascular fusion represents an important mechanism of vessel enlargement during development; however, its significance in postnatal vessel enlargement is still unknown. During fusion, 2 adjoining vessels merge to share 1 larger lumen. The aim of this research was to identify the molecular mechanism responsible for vascular fusion.Approach and Results: We previously showed that both low shear stress and DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) treatment in the embryo result in a hyperfused vascular plexus and that increasing shear stress levels could prevent DAPT-induced fusion. We, therefore, investigated vascular endothelial-cadherin (VEC) phosphorylation because this is a common downstream target of low shear stress and DAPT treatment. VEC phosphorylation increases after DAPT treatment and decreased shear stress. The increased phosphorylation occurred independent of the cleavage of the Notch intracellular domain. Increasing shear stress rescues hyperfusion by DAPT treatment by causing the association of the phosphatase vascular endothelial-protein tyrosine phosphatase with VEC, counteracting VEC phosphorylation. Finally, Src (proto-oncogene tyrosine-protein kinase Src) inhibition prevents VEC phosphorylation in endothelial cells and can rescue hyperfusion induced by low shear stress and DAPT treatment. Moesin, a VEC target that was previously reported to mediate endothelial cell rearrangement during lumenization, relocalizes to cell membranes in vascular beds undergoing hyperfusion.Conclusions: This study provides the first evidence that VEC phosphorylation, induced by DAPT treatment and low shear stress, is involved in the process of fusion during vascular remodeling.
30.	Caolo, V., et al. (author) Shear stress, notch and VE-cadherin : the molecular mechanism of vascular fusion 2018 In: Cardiovascular Research. - : OXFORD UNIV PRESS. - 0008-6363 .- 1755-3245. ; 114, s. S13-S13 Journal article (other academic/artistic)
31.	Cébe-Suarez, Stéphanie, et al. (author) Orf virus VEGF-E NZ2 promotes paracellular NRP-1/VEGFR-2 coreceptor assembly via the peptide RPPR 2008 In: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 22:8, s. 3078-3086 Journal article (peer-reviewed)abstract Vascular endothelial growth factors (VEGFs) interact with the receptor tyrosine kinases (RTKs) VEGFR-1, -2, and -3; neuropilins (NRPs); and heparan sulfate (HS) proteoglycans. VEGF RTKs signal to downstream targets upon ligand-induced tyrosine phosphorylation, while NRPs and HS act as coreceptors that lack enzymatic activity yet modulate signal output by VEGF RTKs. VEGFs exist in various isoforms with distinct receptor specificity and biological activity. Here, a series of mammalian VEGF-A splice variants and orf virus VEGF-Es, as well as chimeric and mutant VEGF variants, were characterized to determine the motifs required for binding to NRP-1 in the absence (VEGF-E) or presence (VEGF-A(165)) of an HS-binding sequence. We identified the carboxyterminal peptides RPPR and DKPRR as the NRP-1 binding motifs of VEGF-E and VEGF-A, respectively. RPPR had significantly higher affinity for NRP-1 than DKPRR. VEGFs containing an RPPR motif promoted HS-independent coreceptor complex assembly between VEGFR-2 and NRP-1, independent of whether these receptors were expressed on the same or separate cells grown in cocultures. Functional studies showed that stable coreceptor assembly by VEGF correlated with its ability to promote vessel formation in an embryoid body angiogenesis assay.
32.	Claesson-Welsh, Lena (author) ADAM-mediated shedding, a new flavor in angiogenesis regulation 2010 In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 30:11, s. 2087-2088 Journal article (other academic/artistic)
33.	Claesson-Welsh, Lena (author) Alk1 (Activin Receptor-Like Kinase 1) and Vascular Hyperpermeability in Diabetic Retinopathy : More Is Less 2018 In: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 38:8, s. 1673-1675 Journal article (other academic/artistic)
34.	Claesson-Welsh, Lena (author) Blood vessels as targets in tumor therapy 2012 In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 117:2, s. 178-186 Research review (peer-reviewed)abstract The landmark papers published by Judah Folkman in the early 1970s on tumor angiogenesis and therapeutic implications promoted the rapid development of a very dynamic field where basic scientists, oncologists, and pharmaceutical industry joined forces to determine the molecular mechanisms in blood vessel formation and find means to exploit this knowledge in suppressing tumor vascularization and growth. A wealth of information has been collected on angiogenic growth factors, and in 2004 the first specific blood vessel-targeted cancer therapy was introduced: a neutralizing antibody against vascular endothelial growth factor (VEGF). Now (2011) we know that suppression of tumor angiogenesis may be a double-edged sword and that the therapy needs to be further refined and individualized. This review describes the hallmarks of tumor vessels, how different angiogenic growth factors exert their function, and the perspectives for future development of anti-angiogenic therapy.
35.	Claesson-Welsh, Lena (author) Gremlin : vexing VEGF receptor agonist 2010 In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 116:18, s. 3386-3387 Journal article (other academic/artistic)abstract Gremlins are mischievous creatures in English folklore, believed to be the cause of otherwise unexplainable breakdowns (the word gremlins is derived from the Old English “gremian” or “gremman,” “to vex”). Gremlin (or Gremlin-1) is also the designation of a secreted protein that is known to regulate bone formation during development. In this issue of Blood, Mitola et al report the novel role of Gremlin as a VEGFR2 agonist1 and the function of the Gremlin protein seems vexing indeed.
36.	Claesson-Welsh, Lena (author) Healing hemangiomas 2008 In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 14:11, s. 1147-8 Journal article (other academic/artistic)
37.	Claesson-Welsh, Lena (author) How the matrix metalloproteinase MMP14 contributes to the progression of colorectal cancer : Comment 2020 In: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 130:3, s. 1093-1095 Journal article (other academic/artistic)abstract Certain matrix metalloproteinase (MMP) family proteins have been associated with cell proliferation and invasion in aggressive cancers. However, attempts to target the MMPs with the hope of treating tumors have thus far failed. In this issue of the JCI, Ragusa and coworkers identified an intestinal cancer subgroup of slow-growing, chemotherapy-resistant, and very aggressive matrix-rich tumors that mimic a hard-to-treat colorectal cancer subtype in humans. These tumors showed downregulated levels of the transcription factor prospero homeobox protein 1 (PROX1), which relieved repression of the matrix metalloproteinase MMP14. Upregulated MMP14 levels correlated with blood vessel dysfunction and a lack of cytotoxic T cells. Notably, blockade of proangiogenic factors in combination with stimulation of the CD40 pathway in the mouse cancer model boosted cytotoxic T cell infiltration. The study illustrates how combinatorial treatments for aggressive, T cell-deficient cancers can launch an antitumor immune response.
38.	Claesson-Welsh, Lena (author) Introduction to symposium on vascular biology, metabolism and cancer 2013 In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 273:2, s. 112-113 Journal article (peer-reviewed)
39.	Claesson-Welsh, Lena, et al. (author) Introduction to the ECR special angiogenesis issue 2013 In: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 319:9, s. 1239-1239 Journal article (other academic/artistic)
40.	Claesson-Welsh, Lena (author) New Frontiers in VEGF/VEGFR Biology 2015 In: Journal of Vascular Research. - 1018-1172 .- 1423-0135. ; 52, s. 79-79 Journal article (other academic/artistic)
41.	Claesson-Welsh, Lena (author) On the physiology of vascular permeability 2015 In: Acta Physiologica. - 1748-1708 .- 1748-1716. ; 215, s. 19-19 Journal article (other academic/artistic)
42.	Claesson-Welsh, Lena (author) Oxygen sensing : a stunningly elegant molecular machinery highjacked in cancer 2020 In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 125:3, s. 205-210 Research review (peer-reviewed)abstract Oxygen is of fundamental importance for most living organisms, and the maintenance of oxygen homeostasis is a key physiological challenge for all large animals. Oxygen deprivation, hypoxia, is a critical component of many human diseases including cancer, heart disease, stroke, vascular disease, and anaemia. The discovery of oxygen sensing provides fundamental knowledge of a stunningly elegant molecular machinery; it also promises development of new therapeutics for serious diseases such as cancer. As a result of their impressive contributions to our understanding of the mechanisms by which cells sense oxygen and signal in hypoxia, Gregg Semenza, Peter Ratcliffe, and William Kaelin were awarded the Nobel Prize in 2019.
43.	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.
44.	Claesson-Welsh, Lena (author) Receptor Talk and Tumor Cell Walk in Glioblastoma 2012 In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 22:1, s. 1-2 Journal article (other academic/artistic)abstract In this issue of Cancer Cell, Lu et al. describe unconventional molecular interactions in glioblastoma cells that provide a mechanism for how anti-vascular endothelial growth factor therapy may promote mesenchymal transition of glioblastoma cells and increase tumor invasion.
45.	Claesson-Welsh, Lena (author) Signal transduction by vascular endothelial growth factor receptors 2012 In: Vascular pharmacology. - : Elsevier BV. - 1537-1891 .- 1879-3649. ; 56:5-6, s. 308-308 Journal article (other academic/artistic)
46.	Claesson-Welsh, Lena, et al. (author) Tracheobronchial transplantation : The Royal Swedish Academy of Sciences' concerns 2016 In: The Lancet. - 0140-6736 .- 1474-547X. ; 387:10022, s. 942-942 Journal article (peer-reviewed)
47.	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.
48.	Claesson-Welsh, Lena (author) Vascular permeability - the essentials 2015 In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 120:3, s. 135-143 Research review (peer-reviewed)abstract The vasculature, composed of vessels of different morphology and function, distributes blood to all tissues and maintains physiological tissue homeostasis. In pathologies, the vasculature is often affected by, and engaged in, the disease process. This may result in excessive formation of new, unstable, and hyperpermeable vessels with poor blood flow, which further promotes hypoxia and disease propagation. Chronic vessel permeability may also facilitate metastatic spread of cancer. Thus, there is a strong incentive to learn more about an important aspect of vessel biology in health and disease: the regulation of vessel permeability. The current review aims to summarize current insights into different mechanisms of vascular permeability, its regulatory factors, and the consequences for disease.
49.	Claesson-Welsh, Lena (author) VEGF-B taken to our hearts : specific effect of VEGF-B in myocardial ischemia 2008 In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 28:9, s. 1575-6 Journal article (other academic/artistic)
50.	Claesson-Welsh, Lena (author) VEGF receptor signal transduction - A brief update 2016 In: Vascular pharmacology. - : Elsevier BV. - 1537-1891 .- 1879-3649. ; 86, s. 14-17 Research review (peer-reviewed)abstract Vascular endothelial growth factor (VEGF) signal transduction through receptor tyrosine lcinases VEGF receptor 1, -2 and -3 is of crucial importance for monocytes/macrophages, blood vascular endothelial and lymphatic endothelial cells both in physiology and in a number of pathologies notably cancer. This brief review summarizes the current status of VEGF receptor signaling with emphasis on in vivo data.

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