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2.
Circ Res ; 126(2): 243-257, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31805812

RESUMO

RATIONALE: ENG (endoglin) is a coreceptor for BMP (bone morphogenetic protein) 9/10 and is strongly expressed in endothelial cells. Mutations in ENG lead to the inherited vascular disorder hereditary hemorrhagic telangiectasia characterized by local telangiectases and larger arteriovenous malformations (AVMs); but how ENG functions to regulate the adult vasculature is not understood. OBJECTIVE: The goal of the work was to determine how ENG maintains vessel caliber in adult life to prevent AVM formation and thereby protect heart function. METHODS AND RESULTS: Genetic depletion of endothelial Eng in adult mice led to a significant reduction in mean aortic blood pressure. There was no evidence of hemorrhage, anemia, or AVMs in major organs to explain the reduced aortic pressure. However, large AVMs developed in the peripheral vasculature intimately associated with the pelvic cartilaginous symphysis-a noncapsulated cartilage with a naturally high endogenous expression of VEGF (vascular endothelial growth factor). The increased blood flow through these peripheral AVMs explained the drop in aortic blood pressure and led to increased cardiac preload, and high stroke volumes, ultimately resulting in high-output heart failure. Development of pelvic AVMs in this region of high VEGF expression occurred because loss of ENG in endothelial cells leads to increased sensitivity to VEGF and a hyperproliferative response. Development of AVMs and associated progression to high-output heart failure in the absence of endothelial ENG was attenuated by targeting VEGF signaling with an anti-VEGFR2 (VEGF receptor 2) antibody. CONCLUSIONS: ENG promotes the normal balance of VEGF signaling in quiescent endothelial cells to maintain vessel caliber-an essential function in conditions of increased VEGF expression such as local hypoxia or inflammation. In the absence of endothelial ENG, increased sensitivity to VEGF drives abnormal endothelial proliferation in local regions of high VEGF expression, leading to AVM formation and a rapid injurious impact on heart function.


Assuntos
Malformações Arteriovenosas/metabolismo , Endoglina/genética , Endotélio Vascular/metabolismo , Insuficiência Cardíaca/etiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Malformações Arteriovenosas/complicações , Malformações Arteriovenosas/genética , Malformações Arteriovenosas/patologia , Pressão Sanguínea , Proliferação de Células , Endoglina/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Endotélio Vascular/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
3.
Sci Rep ; 8(1): 10672, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30006556

RESUMO

Establishment of the functional blood vasculature involves extensive cellular rearrangement controlled by growth factors, chemokines and flow-mediated shear forces. To record these highly dynamic processes in mammalians has been technically demanding. Here we apply confocal and wide field time-lapse in vivo microscopy to characterize the remodelling vasculature of the wounded mouse cornea. Using mouse lines with constitutive or inducible endogenous fluorescent reporters, in combination with tracer injections and mosaic genetic recombination, we follow processes of sprouting angiogenesis, sprout fusion, vessel expansion and pruning in vivo, at subcellular resolution. We describe the migratory behaviour of endothelial cells of perfused vessels, in relation to blood flow directionality and vessel identity. Live-imaging following intravascular injection of fluorescent tracers, allowed for recording of VEGFA-induced permeability. Altogether, live-imaging of the remodelling vasculature of inflamed corneas of mice carrying endogenous fluorescent reporters and conditional alleles, constitutes a powerful platform for investigation of cellular behaviour and vessel function.


Assuntos
Córnea/irrigação sanguínea , Lesões da Córnea/patologia , Neovascularização Patológica/diagnóstico por imagem , Remodelação Vascular , Animais , Córnea/diagnóstico por imagem , Córnea/patologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Genes Reporter/genética , Humanos , Microscopia Intravital , Proteínas Luminescentes/química , Proteínas Luminescentes/genética , Masculino , Camundongos , Microscopia Confocal , Microscopia de Fluorescência , Neovascularização Patológica/patologia , Permeabilidade/efeitos dos fármacos , Imagem com Lapso de Tempo , Fator A de Crescimento do Endotélio Vascular/administração & dosagem
4.
Development ; 144(19): 3590-3601, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28851707

RESUMO

Tissue fluid drains through blind-ended lymphatic capillaries, via smooth muscle cell (SMC)-covered collecting vessels into venous circulation. Both defective SMC recruitment to collecting vessels and ectopic recruitment to lymphatic capillaries are thought to contribute to vessel failure, leading to lymphedema. However, mechanisms controlling lymphatic SMC recruitment and its role in vessel maturation are unknown. Here, we demonstrate that platelet-derived growth factor B (PDGFB) regulates lymphatic SMC recruitment in multiple vascular beds. PDGFB is selectively expressed by lymphatic endothelial cells (LECs) of collecting vessels. LEC-specific deletion of Pdgfb prevented SMC recruitment causing dilation and failure of pulsatile contraction of collecting vessels. However, vessel remodelling and identity were unaffected. Unexpectedly, Pdgfb overexpression in LECs did not induce SMC recruitment to capillaries. This was explained by the demonstrated requirement of PDGFB extracellular matrix (ECM) retention for lymphatic SMC recruitment, and the low presence of PDGFB-binding ECM components around lymphatic capillaries. These results demonstrate the requirement of LEC-autonomous PDGFB expression and retention for SMC recruitment to lymphatic vessels, and suggest an ECM-controlled checkpoint that prevents SMC investment of capillaries, which is a common feature in lymphedematous skin.


Assuntos
Células Endoteliais/metabolismo , Vasos Linfáticos/anatomia & histologia , Vasos Linfáticos/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Animais , Animais Recém-Nascidos , Capilares/metabolismo , Comunicação Celular , Derme/metabolismo , Matriz Extracelular/metabolismo , Feminino , Membro Posterior/metabolismo , Masculino , Mesentério/metabolismo , Morfogênese , Tamanho do Órgão
5.
Nat Cell Biol ; 19(6): 653-665, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28530658

RESUMO

The hierarchical organization of properly sized blood vessels ensures the correct distribution of blood to all organs of the body, and is controlled via haemodynamic cues. In current concepts, an endothelium-dependent shear stress set point causes blood vessel enlargement in response to higher flow rates, while lower flow would lead to blood vessel narrowing, thereby establishing homeostasis. We show that during zebrafish embryonic development increases in flow, after an initial expansion of blood vessel diameters, eventually lead to vessel contraction. This is mediated via endothelial cell shape changes. We identify the transforming growth factor beta co-receptor endoglin as an important player in this process. Endoglin mutant cells and blood vessels continue to enlarge in response to flow increases, thus exacerbating pre-existing embryonic arterial-venous shunts. Together, our data suggest that cell shape changes in response to biophysical cues act as an underlying principle allowing for the ordered patterning of tubular organs.


Assuntos
Forma Celular , Endoglina/metabolismo , Células Endoteliais/metabolismo , Hemodinâmica , Mecanotransdução Celular , Proteínas de Peixe-Zebra/metabolismo , Animais , Malformações Arteriovenosas/genética , Malformações Arteriovenosas/metabolismo , Malformações Arteriovenosas/fisiopatologia , Endoglina/deficiência , Endoglina/genética , Predisposição Genética para Doença , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos Knockout , Mutação , Neovascularização Fisiológica , Fenótipo , Fluxo Sanguíneo Regional , Estresse Mecânico , Fatores de Tempo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
6.
Nat Cell Biol ; 19(6): 639-652, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28530660

RESUMO

Loss-of-function (LOF) mutations in the endothelial cell (EC)-enriched gene endoglin (ENG) cause the human disease hereditary haemorrhagic telangiectasia-1, characterized by vascular malformations promoted by vascular endothelial growth factor A (VEGFA). How ENG deficiency alters EC behaviour to trigger these anomalies is not understood. Mosaic ENG deletion in the postnatal mouse rendered Eng LOF ECs insensitive to flow-mediated venous to arterial migration. Eng LOF ECs retained within arterioles acquired venous characteristics and secondary ENG-independent proliferation resulting in arteriovenous malformation (AVM). Analysis following simultaneous Eng LOF and overexpression (OE) revealed that ENG OE ECs dominate tip-cell positions and home preferentially to arteries. ENG knockdown altered VEGFA-mediated VEGFR2 kinetics and promoted AKT signalling. Blockage of PI(3)K/AKT partly normalized flow-directed migration of ENG LOF ECs in vitro and reduced the severity of AVM in vivo. This demonstrates the requirement of ENG in flow-mediated migration and modulation of VEGFR2 signalling in vascular patterning.


Assuntos
Malformações Arteriovenosas/prevenção & controle , Endoglina/metabolismo , Células Endoteliais/metabolismo , Neovascularização Patológica , Neovascularização Fisiológica , Transdução de Sinais , Telangiectasia Hemorrágica Hereditária/prevenção & controle , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Malformações Arteriovenosas/genética , Malformações Arteriovenosas/metabolismo , Malformações Arteriovenosas/patologia , Linhagem da Célula , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Endoglina/deficiência , Endoglina/genética , Células Endoteliais/patologia , Predisposição Genética para Doença , Humanos , Cinética , Camundongos Knockout , Fenótipo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Estresse Mecânico , Telangiectasia Hemorrágica Hereditária/genética , Telangiectasia Hemorrágica Hereditária/metabolismo , Telangiectasia Hemorrágica Hereditária/patologia , Técnicas de Cultura de Tecidos , Transfecção , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
7.
J Cell Sci ; 130(8): 1365-1378, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28254885

RESUMO

Platelet-derived growth factor (PDGF)-D is a PDGF receptor ß (PDGFRß)-specific ligand implicated in a number of pathological conditions, such as cardiovascular disease and cancer, but its biological function remains incompletely understood. In this study, we demonstrate that PDGF-D binds directly to neuropilin 1 (NRP1), in a manner that requires the PDGF-D C-terminal Arg residue. Stimulation with PDGF-D, but not PDGF-B, induced PDGFRß-NRP1 complex formation in fibroblasts. Additionally, PDGF-D induced translocation of NRP1 to cell-cell junctions in endothelial cells, independently of PDGFRß, altering the availability of NRP1 for VEGF-A-VEGFR2 signaling. PDGF-D showed differential effects on pericyte behavior in ex vivo sprouting assays compared to PDGF-B. Furthermore, PDGF-D-induced PDGFRß-NRP1 interaction can occur in trans between molecules located in different cells (endothelial cells and pericytes). In summary, we show that NRP1 can act as a co-receptor for PDGF-D-PDGFRß signaling and is possibly implicated in intercellular communication in the vascular wall.


Assuntos
Doenças Cardiovasculares/metabolismo , Endotélio Vascular/metabolismo , Fibroblastos/metabolismo , Junções Intercelulares/metabolismo , Neoplasias/metabolismo , Neuropilina-1/metabolismo , Pericitos/metabolismo , Animais , Linhagem Celular Transformada , Humanos , Linfocinas/metabolismo , Neovascularização Fisiológica , Fator de Crescimento Derivado de Plaquetas/metabolismo , Ligação Proteica , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Suínos
8.
Sci Signal ; 9(438): ra76, 2016 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-27460990

RESUMO

Spontaneous neural differentiation of embryonic stem cells is induced by Noggin-mediated inhibition of bone morphogenetic protein 4 (BMP4) signaling. RhoA is a guanosine triphosphatase (GTPase) that regulates cytoskeletal dynamics and gene expression, both of which control stem cell fate. We found that disruption of Syx, a gene encoding a RhoA-specific guanine nucleotide exchange factor, accelerated retinoic acid-induced neural differentiation in murine embryonic stem cells aggregated into embryoid bodies. Cells from Syx(+/+) and Syx(-/-) embryoid bodies had different abundances of proteins implicated in stem cell pluripotency. The differentiation-promoting proteins Noggin and RARγ (a retinoic acid receptor) were more abundant in cells of Syx(-/-) embryoid bodies, whereas the differentiation-suppressing proteins SIRT1 (a protein deacetylase) and the phosphorylated form of SMAD1 (the active form of this transcription factor) were more abundant in cells of Syx(+/+) embryoid bodies. These differences were blocked by the overexpression of constitutively active RhoA, indicating that the abundance of these proteins was maintained, at least in part, by RhoA activity. The peripheral stress fibers in cells from Syx(-/-) embryoid bodies were thinner than those in Syx(+/+) cells. Furthermore, less Noggin and fewer vesicles containing Rab3d, a GTPase that mediates Noggin trafficking, were detected in cells from Syx(-/-) embryoid bodies, which could result from increased Noggin exocytosis. These results suggested that, in addition to inhibiting Noggin transcription, RhoA activity in wild-type murine embryonic stem cells also prevented neural differentiation by limiting Noggin secretion.


Assuntos
Diferenciação Celular/fisiologia , Células-Tronco Embrionárias Murinas/metabolismo , Neurônios/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Camundongos , Camundongos Knockout , Células-Tronco Embrionárias Murinas/citologia , Neurônios/citologia , Transcrição Genética/fisiologia , Proteínas rab3 de Ligação ao GTP/genética , Proteínas rab3 de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP
9.
Biochem Soc Trans ; 42(6): 1576-83, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25399573

RESUMO

The blood vasculature is constantly adapting to meet the demand from tissue. In so doing, branches may form, reorganize or regress. These complex processes employ integration of multiple signalling cascades, some of them being restricted to endothelial and mural cells and, hence, suitable for targeting of the vasculature. Both genetic and drug targeting experiments have demonstrated the requirement for the vascular endothelial growth factor (VEGF) system, the Delta-like-Notch system and the transforming growth factor ß (TGFß)/bone morphogenetic protein (BMP) cascades in vascular development. Although several of these signalling cascades in part converge into common downstream components, they differ in temporal and spatial regulation and expression. For example, the pro-angiogenic VEGFA is secreted by cells in need of oxygen, presented to the basal side of the endothelium, whereas BMP9 and BMP10 are supplied via the bloodstream in constant interaction with the apical side to suppress angiogenesis. Delta-like 4 (DLL4), on the other hand, is provided as an endothelial membrane bound ligand. In the present article, we discuss recent data on the integration of these pathways in the process of sprouting angiogenesis and vascular patterning and malformation.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Neovascularização Fisiológica , Receptores Notch/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Humanos
10.
Int J Radiat Biol ; 90(9): 778-89, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24913294

RESUMO

PURPOSE: To investigate the effects of cranial irradiation on the neurovascular niche in the young brain. Disruption of this niche has previously been observed in the adult rat brain after irradiation. MATERIALS AND METHODS: We subjected postnatal day 14 (P14) mice to a single dose of 8 Gy whole brain irradiation and measured the distance between microvessels and either neural progenitor cells (doublecortin-positive, DCX(+)) or proliferating cells (Ki-67(+)) in the dorsal hippocampal subgranular zone (SGZ) 6 hours, 1 week and 7 weeks post-irradiation. In addition, pericyte coverage of microvessels in the SGZ was measured. RESULTS: DCX(+) and Ki-67(+) cells were located closer to microvessels in the adult brain compared to young, still growing brains, constituting new information on normal development. We found an increased distance between microvessels and DCX(+) cells 6 h post-irradiation and between microvessels and Ki-67(+) cells 1 week post-irradiation. Furthermore, pericyte coverage was transiently decreased by 17% 6 h post-irradiation. CONCLUSIONS: The hippocampal neurovascular niche in the young, growing brain is transiently disrupted by irradiation. It remains to be elucidated what role these transient changes play in the apparently permanent ablation of hippocampal neurogenesis previously demonstrated in the same model.


Assuntos
Encéfalo/efeitos da radiação , Hipocampo/efeitos da radiação , Neurogênese/fisiologia , Animais , Encéfalo/crescimento & desenvolvimento , Morte Celular , Proliferação de Células , Giro Denteado/efeitos da radiação , Hipocampo/crescimento & desenvolvimento , Antígeno Ki-67/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microcirculação , Neurônios/efeitos da radiação , Aceleradores de Partículas , Pericitos/citologia , Radioterapia , Ratos , Fatores de Tempo
11.
Exp Cell Res ; 319(9): 1264-70, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23454603

RESUMO

Blood vessels are composed of endothelial cells, mural cells (smooth muscle cells and pericytes) and their shared basement membrane. During embryonic development a multitude of signaling components orchestrate the formation of new vessels. The process is highly dependent on correct dosage, spacing and timing of these signaling molecules. As vessels mature some cascades remain active, albeit at very low levels, and may be reactivated upon demand. Members of the Transforming growth factor ß (TGF-ß) protein family are strongly engaged in developmental angiogenesis but are also regulators of vascular integrity in the adult. In humans various genetic alterations within this protein family cause vascular disorders, involving disintegration of vascular integrity. Here we summarize and discuss recent data gathered from conditional and endothelial cell specific genetic loss-of-function of members of the TGF-ß family in the mouse.


Assuntos
Proteínas da Superfamília de TGF-beta/genética , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiopatologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Deleção de Genes , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Proteínas da Superfamília de TGF-beta/metabolismo , Proteínas da Superfamília de TGF-beta/fisiologia
12.
Dev Cell ; 23(3): 587-99, 2012 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-22975327

RESUMO

Angiogenesis, the process by which new blood vessels arise from preexisting ones, is critical for embryonic development and is an integral part of many disease processes. Recent studies have provided detailed information on how angiogenic sprouts initiate, elongate, and branch, but less is known about how these processes cease. Here, we show that S1PR1, a receptor for the blood-borne bioactive lipid sphingosine-1-phosphate (S1P), is critical for inhibition of angiogenesis and acquisition of vascular stability. Loss of S1PR1 leads to increased endothelial cell sprouting and the formation of ectopic vessel branches. Conversely, S1PR1 signaling inhibits angiogenic sprouting and enhances cell-to-cell adhesion. This correlates with inhibition of vascular endothelial growth factor-A (VEGF-A)-induced signaling and stabilization of vascular endothelial (VE)-cadherin localization at endothelial junctions. Our data suggest that S1PR1 signaling acts as a vascular-intrinsic stabilization mechanism, protecting developing blood vessels against aberrant angiogenic responses.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Neovascularização Fisiológica , Receptores de Lisoesfingolipídeo/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Células Cultivadas , Células Endoteliais/metabolismo , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Receptores de Lisoesfingolipídeo/deficiência , Receptores de Esfingosina-1-Fosfato , Peixe-Zebra
13.
Ambio ; 41(2): 138-50, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22396094

RESUMO

Bathymetry, the underwater topography, is a fundamental property of oceans, seas, and lakes. As such it is important for a wide range of applications, like physical oceanography, marine geology, geophysics and biology or the administration of marine resources. The exact requirements users may have regarding bathymetric data are, however, unclear. Here, the results of a questionnaire survey and a literature review are presented, concerning the use of Baltic Sea bathymetric data in research and for societal needs. It is demonstrated that there is a great need for detailed bathymetric data. Despite the abundance of high-quality bathymetric data that are produced for safety of navigation purposes, the digital bathymetric models publicly available to date cannot satisfy this need. Our study shows that DBMs based on data collected for safety of navigation could substantially improve the base data for administrative decision making as well as the possibilities for marine research in the Baltic Sea.


Assuntos
Oceanografia , Países Bálticos , Bases de Dados Factuais , Oceanos e Mares , Países Escandinavos e Nórdicos , Inquéritos e Questionários
14.
Arterioscler Thromb Vasc Biol ; 32(5): 1255-63, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22345168

RESUMO

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, transforming growth factor ß, 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 transforming growth factor ß 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.


Assuntos
Endotélio Vascular/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Neovascularização Patológica/metabolismo , Proteoglicanas/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Animais , Western Blotting , Adesão Celular/efeitos dos fármacos , Proliferação de Células , Células Cultivadas , Condroitina , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Imuno-Histoquímica , Camundongos , Neovascularização Patológica/induzido quimicamente , Neovascularização Patológica/patologia , Transdução de Sinais/efeitos dos fármacos
15.
Cancers (Basel) ; 4(2): 400-19, 2012 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-24213317

RESUMO

The blood vasculature in cancers has been the subject of intense interest during the past four decades. Since the original ideas of targeting angiogenesis to treat cancer were proposed in the 1970s, it has become evident that more knowledge about the role of vessels in tumor biology is needed to fully take advantage of such strategies. The vasculature serves the surrounding tissue in a multitude of ways that all must be taken into consideration in therapeutic manipulation. Aspects of delivery of conventional cytostatic drugs, induction of hypoxia affecting treatment by radiotherapy, changes in tumor cell metabolism, vascular leak and trafficking of leukocytes are affected by interventions on vascular function. Many tumors constitute a highly interchangeable milieu undergoing proliferation, apoptosis, and necrosis with abundance of growth factors, enzymes and metabolites. These aspects are reflected by the abnormal tortuous, leaky vascular bed with detached mural cells (pericytes). The vascular bed of tumors is known to be unstable and undergoing remodeling, but it is not until recently that this has been dynamically demonstrated at high resolution, facilitated by technical advances in intravital microscopy. In this review we discuss developmental genetic loss-of-function experiments in the light of tumor angiogenesis. We find this a valid comparison since many studies phenocopy the vasculature in development and tumors.

16.
Nat Cell Biol ; 13(10): 1202-13, 2011 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-21909098

RESUMO

Angiogenesis, the growth of new blood vessels, involves specification of endothelial cells to tip cells and stalk cells, which is controlled by Notch signalling, whereas vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 have been implicated in angiogenic sprouting. Surprisingly, we found that endothelial deletion of Vegfr3, but not VEGFR-3-blocking antibodies, postnatally led to excessive angiogenic sprouting and branching, and decreased the level of Notch signalling, indicating that VEGFR-3 possesses passive and active signalling modalities. Furthermore, macrophages expressing the VEGFR-3 and VEGFR-2 ligand VEGF-C localized to vessel branch points, and Vegfc heterozygous mice exhibited inefficient angiogenesis characterized by decreased vascular branching. FoxC2 is a known regulator of Notch ligand and target gene expression, and Foxc2(+/-);Vegfr3(+/-) compound heterozygosity recapitulated homozygous loss of Vegfr3. These results indicate that macrophage-derived VEGF-C activates VEGFR-3 in tip cells to reinforce Notch signalling, which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts.


Assuntos
Células Endoteliais/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Fisiológica , Receptores Notch/metabolismo , Vasos Retinianos/metabolismo , Rombencéfalo/irrigação sanguínea , Transdução de Sinais , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Anticorpos/farmacologia , Linhagem Celular Tumoral , Células Endoteliais/efeitos dos fármacos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Neovascularização Patológica/genética , Neovascularização Fisiológica/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , Receptores Notch/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transdução Genética , Transfecção , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator B de Crescimento do Endotélio Vascular/genética , Fator B de Crescimento do Endotélio Vascular/metabolismo , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/metabolismo , Fator D de Crescimento do Endotélio Vascular/genética , Fator D de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/deficiência , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética
17.
Nat Cell Biol ; 12(10): 943-53, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20871601

RESUMO

Sprouting angiogenesis requires the coordinated behaviour of endothelial cells, regulated by Notch and vascular endothelial growth factor receptor (VEGFR) signalling. Here, we use computational modelling and genetic mosaic sprouting assays in vitro and in vivo to investigate the regulation and dynamics of endothelial cells during tip cell selection. We find that endothelial cells compete for the tip cell position through relative levels of Vegfr1 and Vegfr2, demonstrating a biological role for differential Vegfr regulation in individual endothelial cells. Differential Vegfr levels affect tip selection only in the presence of a functional Notch system by modulating the expression of the ligand Dll4. Time-lapse microscopy imaging of mosaic sprouts identifies dynamic position shuffling of tip and stalk cells in vitro and in vivo, indicating that the VEGFR-Dll4-Notch signalling circuit is constantly re-evaluated as cells meet new neighbours. The regular exchange of the leading tip cell raises novel implications for the concept of guided angiogenic sprouting.


Assuntos
Células Endoteliais/citologia , Células Endoteliais/metabolismo , Neovascularização Fisiológica/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas de Ligação ao Cálcio , Biologia Computacional , Simulação por Computador , Drosophila/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores Notch/metabolismo , Vasos Retinianos/metabolismo , Transdução de Sinais , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra/embriologia
18.
Biochem Soc Trans ; 37(Pt 6): 1233-6, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19909253

RESUMO

ECs (endothelial cells) in the developing vasculature are heterogeneous in morphology, function and gene expression. Inter-endothelial signalling via Dll4 (Delta-like 4) and Notch has recently emerged as a key regulator of endothelial heterogeneity, controlling arterial cell specification and tip versus stalk cell selection. During sprouting angiogenesis, tip cell formation is the default response to VEGF (vascular endothelial growth factor), whereas the stalk cell phenotype is acquired through Dll4/Notch-mediated lateral inhibition. Precisely how Notch signalling represses stalk cells from becoming tip cells remains unclear. Multiple components of the VEGFR (VEGF receptor) system are regulated by Notch, suggesting that quantitative differences in protein expression between adjacent ECs may provide key features in the formation of a functional vasculature. Computational modelling of this selection process in iterations, with experimental observation and validation greatly facilitates our understanding of the integrated processes at the systems level. We anticipate that the study of mosaic vascular beds of genetically modified ECs in dynamic interactions with wild-type ECs will provide a powerful tool for the investigation of the molecular control and cellular mechanisms of EC specification.


Assuntos
Vasos Sanguíneos , Neovascularização Fisiológica/fisiologia , Receptores Notch/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Vasos Sanguíneos/anatomia & histologia , Vasos Sanguíneos/fisiologia , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Receptores Notch/genética , Transdução de Sinais/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética
20.
ScientificWorldJournal ; 8: 1246-9, 2008 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-19082420

RESUMO

Angiogenesis is crucial in the progression of a number of pathological conditions, such as diabetic retinopathy, rheumatoid arthritis, psoriasis, and cancer. In contrast to vessels in healthy tissues, the vasculature in these pathologies is highly unstable, constantly dissolving and renewing. Characteristically, vessels in pathologies have discontinuous basement membrane (BM) coverage. The consequences of shifts in BM density and composition are still relatively unknown. Several studies have illustrated that partial loss of the vascular BM during development results in the widening of vessels. This has been suggested to be a result of reduced mechanical resistance to the force inflicted by the blood pressure. However, recent data indicate that depletion of BM laminins (LMs) leads to enlarged vessels even in the absence of cardiac activity and blood pressure. A key question is whether single BM components or fragments thereof play distinct roles in the angiogenic process, or if it is the balance between the different components of the BM that guides the morphology of the new vessel.


Assuntos
Membrana Basal , Neovascularização Fisiológica , Animais , Membrana Basal/citologia , Proliferação de Células
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