the-corneal-micropocket-assay-a-model-of-angiogenesis-in-the-mouse-eye

The Corneal Micropocket Assay: A Model of Angiogenesis in the Mouse Eye

The mouse corneal micropocket assay is a robust and quantitative in vivo assay for evaluating angiogenesis. By using standardized slow-release pellets ...

Boston Children's Hospital

Thalidomide has recently been shown to be useful in the treatment of multiple myeloma and may also be useful in the treatment of other hematological malignancies. We have identified a new derivative of thalidomide, S-3-[3-amino-phthalimido]-glutarimide (S-3APG) with dual activity against B-cell neoplasias. S-3APG was able to directly inhibit the proliferation of myeloma and Burkitt's lymphoma cell lines in vitro without showing toxicity to normal bone marrow stromal cells or hematopoietic progenitor cells. In vivo, S-3APG treatment of drug resistant myeloma cell tumors in mice was able to produce complete and sustained regressions without any observed toxicity. Additionally, S-3APG induced complete regressions of Burkitt's lymphoma cell tumors. Furthermore, S-3APG inhibited angiogenesis more potently than thalidomide in the murine corneal micropocket model. We conclude that S-3APG is a powerful anti-myeloma and anti-B-cell-lymphoma agent that has both antiproliferative and antiangiogenic effects.

S-3-Amino-phthalimido-glutarimide inhibits angiogenesis and growth of B-cell neoplasias in mice.

Angiogenesis is regulated by the balance between angiogenic stimulators and inhibitors. Numerous reports have demonstrated that tumors induce aggressive angiogenesis by up-regulating the production of angiogenesis stimulating growth factors to overcome the baseline levels of endogenous inhibitors. However, the possibility of large differences in the host's responsiveness to angiogenic factors has been largely overlooked. Using the corneal micropocket neovascularization assay, we have observed >10-fold differences in responsiveness to either basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) among various mouse strains. The inheritance pattern observed for these traits supported a QTL (quantitative trait locus) approach to mapping the genes responsible for the differences in angiogenic responsiveness. To overcome variability in the assay, we used recombinant inbred lines to map this phenotype. In the BXD series of recombinant inbred mouse strains, we have mapped the regions responsible for regulating VEGF-induced angiogenesis using both composite interval mapping and multiple interval mapping. Both approaches link VEGF responsiveness to regions on chromosomes 2 (near D2Mit6) and 10 (near D10Mit20). Candidate angiogenesis-related genes in these regions include those for collagen XVIII/endostatin, matrix metalloproteinase 11, integrin beta2, prostaglandin D2 synthase, and interleukin-1 receptor antagonist.

Genetic loci that control vascular endothelial growth factor-induced angiogenesis.

Angiogenesis is controlled by a balance between stimulatory growth factors and endogenous inhibitors. We propose that the balance of stimulators and inhibitors, as well as the general sensitivity of the endothelium to these factors, varies from individual to individual. Indeed, we have found that individual mouse strains have dramatically different responses to growth factor-induced neovascularization. Quantitative trait loci (QTLs), which influence the extent of angiogenesis induced by vascular endothelial growth factor (VEGF), were previously identified by our laboratory. Since genetic susceptibility may vary according to the angiogenic stimulator, we have undertaken a similar mapping approach to identify QTLs that influence basic fibroblast growth factor (FGF2) induced neovascularization in the BXD series of recombinant inbred mouse strains. Composite and multiple interval mapping identified areas of chromosomes 4, 13, 15, and 18. These new angiogenesis QTLs, named AngFq1 through AngFq4 (for angiogenesis due to FGF2), are different from previously identified VEGF QTLs. The mapped regions contain several genes involved in the angiogenic process including matrix metalloproteinase 16, eph receptor A7, angiopoetin 1, endothelial lipase, and autotaxin. Differences in these regions may influence individual susceptibility to angiogenesis related diseases such as cancer, macular degeneration, atherosclerosis, and arthritis.

Genetic loci that control the angiogenic response to basic fibroblast growth factor.

The first recombinant endostatin that elicited strong antitumor activity was expressed in Escherichia coli and administered as a suspension. Under these conditions, the protein retained its full antiangiogenic activity. Lack of requirement for a folded structure prompted us to investigate antitumor properties of synthetic peptides corresponding to different regions of endostatin. Here, we show that the entire antitumor, antimigration, and antipermeability activities of endostatin are mimicked by a 27-amino-acid peptide corresponding to the NH2-terminal domain of endostatin. This peptide contains three histidines that are responsible for zinc binding. Mutations of the zinc-binding histidines abolished its antitumor and antimigration activities, but not antipermeability properties.

A 27-amino-acid synthetic peptide corresponding to the NH2-terminal zinc-binding domain of endostatin is responsible for its antitumor activity.

We evaluated the efficacy of systemic 2-methoxyestradiol (2ME2) in a laser-induced murine model of choroidal neovascularization (CNV). C57BL/6J mice (8-week-old males) were used in this study and divided into four groups. After laser treatment, daily oral treatment with vehicle control, and 30, 50, and 75 mg/kg of 2ME2 was started. Two weeks after laser treatment, digital images of CNV were obtained from fluorescein isothiocyanate-dextran (FITC-dextran) angiography and choroidal flat mount after FITC-dextran perfusion. These images were quantified by NIH image software. Analysis of images from both FITC-dextran angiography and choroidal flat mount with FITC-dextran perfusion demonstrated that the 2ME2 treated groups showed a statistically significant, dose-dependent decrease in CNV. No toxicity or weight loss was observed during the treatment. Significant antiangiogenic effects of oral 2ME2 on laser induced CNV were observed. Since 2ME2 (Panzem) has demonstrated good safety in phase I/II trials for cancer, it has the potential to be used as a novel oral treatment for age-related macular degeneration.

Antiangiogenic effect of oral 2-methoxyestradiol on choroidal neovascularization in mice.

Radiation can potentially suppress neovascularization by inhibiting the incorporation of hematopoietic precursors as well as damaging mature endothelial cells. The purpose of these studies was to quantify the effect of radiation on angiogenesis and to examine the relationship between bone marrow reconstitution and neovascularization. Immune competent, severe combined immunodeficient, RAG1-deficient, and green fluorescence protein transgenic mice in the C57 genetic background, as well as the highly angiogenic 129S1/SvlmJ strain of mice, underwent whole-body or localized exposure to radiation. The hematopoietic systems in the irradiated recipients were restored by bone marrow transfer. Hematopoietic reconstitution was assessed by doing complete blood counts. Angiogenesis was induced in the mouse cornea using 80 ng of purified basic fibroblast growth factor, and the neovascular response was quantified using a slit lamp biomicroscope. Following whole-body exposure and bone marrow transplantation, the hematopoietic system was successfully reconstituted over time, but the corneal angiogenic response was permanently and significantly blunted up to 66%. Localized exposure of the eyes to radiation suppressed corneal angiogenesis comparably to whole-body exposure. Whole-body irradiation with ocular shielding induced bone marrow suppression but did not inhibit corneal neovascularization. In mice exposed to radiation before tumor implantation, the reduced local angiogenic response correlated with significantly reduced growth of tumor cells in vivo. These results indicate that bone marrow suppression does not suppress neovascularization in the mouse cornea and that although hematopoietic stem cells can readily reconstitute peripheral blood, they do not restore a local radiation-induced deficit in neovascular response.

Chronic suppression of angiogenesis following radiation exposure is independent of hematopoietic reconstitution.

Bacillus anthracis protective antigen (PA), the B subunit of the binary anthrax toxin, binds to the cellular receptors capillary morphogenesis gene 2 protein and tumor endothelial marker 8 with high affinity. Both receptors are expressed on endothelial cells during angiogenesis. We sought to determine whether one could inhibit angiogenesis by interfering with the binding of these receptors to their endogenous ligands. Here, we show that wild-type PA inhibits both vascular endothelial growth factor-induced and basic fibroblast growth factor-induced angiogenesis at moderate but statistically significant levels. Structure-activity studies identified a PA mutant that exhibited markedly enhanced inhibition of angiogenesis and also inhibited tumor growth in vivo. This mutant, PASSSR, is unable to undergo normal cellular processing and, thus, remains bound to the surface receptor. Further mutation of PASSSR so that it does not bind to these cell surface receptors abolished its ability to inhibit angiogenesis. We conclude that high-affinity anthrax toxin receptor (ATR) ligands, such as PA and PASSSR, are angiogenesis inhibitors and that ATRs are useful targets for antiangiogenic therapy. These results also suggest that endothelial cell-binding proteins from additional pathogens may inhibit angiogenesis and raise the question of the role of such inhibition in pathogenesis.

Mutant anthrax toxin B moiety (protective antigen) inhibits angiogenesis and tumor growth.

The mouse corneal micropocket angiogenesis assay uses the avascular cornea as a canvas to study angiogenesis in vivo. Through the use of standardized slow-release pellets, a predictable angiogenic response is generated over the course of 5 d and then quantified. Uniform slow-release pellets are prepared by mixing purified angiogenic growth factors such as basic fibroblast growth factor or vascular endothelial growth factor with sucralfate (a stabilizer) and Hydron (poly-HEMA (poly(2-hydroxyethyl methacrylate)) to allow slow release). This mixture is applied to a mesh that controls unit size and then allowed to harden. A micropocket is surgically created in the mouse cornea and a pellet implanted. Five days later, the area of the cornea overgrown by the angiogenic response is measured using a slit lamp. A skilled investigator can implant and grade 40 eyes in about 2.5 h. The results of the assay are used to assess the ability of potential therapeutic molecules or genetic differences to modulate angiogenesis in vivo.

The mouse cornea micropocket angiogenesis assay.

Angiogenesis, the formation of new capillary blood vessels, is an essential biological process under physiological conditions, including embryonic development, reproduction, and wound repair. Under pathologic conditions, this process plays a critical role in a variety of diseases such as cancer, rheumatoid arthritis, atherosclerosis, endometriosis, diabetic retinopathy, and age-related macular degeneration. The purpose of this study was to examine the effects of cyclooxygenase inhibitors on basic fibroblast growth factor (bFGF)- and vascular endothelial growth factor (VEGF)-mediated ocular neovascularization and permeability.

Differential suppression of vascular permeability and corneal angiogenesis by nonsteroidal anti-inflammatory drugs.

Angiogenesis is controlled by a balance between stimulators and inhibitors. We propose that the balance, as well as the general sensitivity of the endothelium to these factors, varies from individual to individual. Indeed, we have found that individual mouse strains have dramatically different responses to growth factor-induced neovascularization. Quantitative trait loci (QTLs), which influence the extent of corneal angiogenesis induced by vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2), were previously identified by our laboratory. To investigate the genetic contribution to choroidal neovascularization (CNV), a leading cause of blindness, we have undertaken a similar mapping approach to identify QTLs that influence laser-induced CNV in the BXD series of recombinant inbred mouse strains. Composite interval mapping identified new angiogenic QTLs on chromosomes 2 and 19, in addition to confirming our previous corneal neovascularization QTLs of AngVq1 and AngFq2. The new QTLs are named AngCNVq1 and AngCNVq2. The newly mapped regions contain several candidate genes involved in the angiogenic process, including thrombospondin 1, delta-like 4, BclII modifying factor, phospholipase C, beta 2, adrenergic receptor, beta 1, actin-binding LIM protein 1 and colony stimulating factor 2 receptor, alpha. Differences in these regions may control individual susceptibility to CNV.

Genetic loci that control the size of laser-induced choroidal neovascularization.

To investigate the antiangiogenesis mechanism of epigallocatechin-3-gallate (EGCG) in an endometriosis model in vivo.

Green tea epigallocatechin-3-gallate inhibits angiogenesis and suppresses vascular endothelial growth factor C/vascular endothelial growth factor receptor 2 expression and signaling in experimental endometriosis in vivo.

Angiogenesis is the process by which new blood vessels are formed from existing vessels. Mammalian populations, including humans and mice, harbor genetic variations that alter angiogenesis. Angiogenesis-regulating gene variants can result in increased susceptibility to multiple angiogenesis-dependent diseases in humans. Our efforts to dissect the complexity of the genetic diversity that regulates angiogenesis have used laboratory animals due to the availability of genome sequence for many species and the ability to perform high volume controlled breeding. Using the murine corneal micropocket assay, we have observed more than ten-fold difference in angiogenic responsiveness among various mouse strains. This degree of difference is observed with either bFGF or VEGF induced corneal neovascularization. Ongoing mapping studies have identified multiple loci that affect angiogenic responsiveness in several mouse models. In this study, we used F2 intercrosses between C57BL/6J and the 129 substrains 129P1/ReJ and 129P3/J, as well as the SJL/J strain, where we have identified new QTLs that affect angiogenic responsiveness. In the case of AngFq5, on chromosome 7, congenic animals were used to confirm the existence of this locus and subcongenic animals, combined with a haplotype-based mapping approach that identified the pink-eyed dilution mutation as a candidate polymorphism to explain AngFq5. The ability of mutations in the pink-eyed dilution gene to affect angiogenic response was demonstrated using the p-J allele at the same locus. Using this allele, we demonstrate that pink-eyed dilution mutations in Oca2 can affect both bFGF and VEGF-induced corneal angiogenesis.

The classical pink-eyed dilution mutation affects angiogenic responsiveness.

Antiangiogenesis therapy has become a vital part of the armamentarium against cancer. Hypertension is a dose-limiting toxicity for VEGF inhibitors. Thus, there is a pressing need to address the associated adverse events so these agents can be better used. The hypertension may be mediated by reduced NO bioavailability resulting from VEGF inhibition. We proposed that the hypertension may be prevented by coadministration with endostatin (ES), an endogenous angiogenesis inhibitor with antitumor effects shown to increase endothelial NO production in vitro. We determined that Fc-conjugated ES promoted NO production in endothelial and smooth muscle cells. ES also lowered blood pressure in normotensive mice and prevented hypertension induced by anti-VEGF antibodies. This effect was associated with higher circulating nitrate levels and was absent in eNOS-knockout mice, implicating a NO-mediated mechanism. Retrospective study of patients treated with ES in a clinical trial revealed a small but significant reduction in blood pressure, suggesting that the findings may translate to the clinic. Coadministration of ES with VEGF inhibitors may offer a unique strategy to prevent drug-related hypertension and enhance antiangiogenic tumor suppression.

Endostatin lowers blood pressure via nitric oxide and prevents hypertension associated with VEGF inhibition.

&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x5F02;&#x4F4D;&#x75C7;&#x662F;&#x4E00;&#x79CD;&#x8840;&#x7BA1;&#x75BE;&#x75C5;&#x3002;&#x8BB8;&#x591A;&#x7814;&#x7A76;&#x8868;&#x660E;&#xFF0C;&#x5BFC;&#x81F4;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x5F02;&#x4F4D;&#x751F;&#x957F;&#xFF0C;&#x4F46;&#x662F;&#x57FA;&#x7840;&#x673A;&#x5236;&#x4ECD;&#x672A;&#x5B8C;&#x5168;&#x4E86;&#x89E3;&#x6291;&#x5236;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x7684;&#x6291;&#x5236;&#x4F5C;&#x7528;&#x3002;&#x6211;&#x4EEC;&#x4EE5;&#x5F80;&#x7684;&#x7814;&#x7A76;&#x8868;&#x660E;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x751F;&#x957F;&#x56E0;&#x5B50; (VEGF-C) C &#x4F5C;&#x4E3A;&#x76EE;&#x6807;&#x7684;&#x6297;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x6CBB;&#x7597;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x5F02;&#x4F4D;&#x75C7;&#x3002;&#x5728;&#x8FD9;&#x9879;&#x7814;&#x7A76;&#xFF0C;&#x5728;&#x5B50;&#x5BAB;&#x5185;&#x819C; VEGF-C &#x548C;&#x5728;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x5F02;&#x4F4D;&#x75C7;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x4E2D;&#x7684;&#x4F5C;&#x7528;&#x8FDB;&#x884C;&#x4E86;&#x7814;&#x7A76;&#x3002;&#x4ECE;&#x5987;&#x5973;&#x4E0E;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x5F02;&#x4F4D;&#x75C7;&#x5206;&#x5B50;&#x7814;&#x7A76;&#x83B7;&#x5F97;&#x4E86;&#x4EBA;&#x7C7B;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x3002;VEGF-B&#x3001; VEGF-C &#x548C; VEGF D mRNA &#x548C;&#x86CB;&#x767D;&#x5728;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x4E2D;&#x7684; VEGF-A &#x88AB;&#x6D4B;&#x91CF;&#x3002;&#x5185;&#x76AE;&#x7EC6;&#x80DE;&#x88AB;&#x8F6C;&#x67D3; VEGF C siRNA &#x4F53;&#x5916;&#xFF0C;&#x5BF9;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x7EC6;&#x80DE;&#x8FC1;&#x79FB;&#x3001; &#x5165;&#x4FB5;&#x548C;&#x7BA1;&#x5F62;&#x6210; VEGF-C &#x7684;&#x5F71;&#x54CD;&#x8FDB;&#x884C;&#x4E86;&#x8C03;&#x67E5;&#x4F53;&#x5916;&#x3002;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x6291;&#x5236;&#x4F5C;&#x7528;&#xFF0C;&#x91CE;&#x751F;&#x578B;&#x5C0F;&#x9F20;&#x3001; &#x771F;&#x76AE;&#x76AE;&#x80A4;&#x8840;&#x7BA1;&#x901A;&#x900F;&#x6027;&#x786E;&#x5B9A;&#x4F53;&#x5185;&#x3002;&#x79FB;&#x690D;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x963B;&#x788D;&#x4E86;&#x514D;&#x75AB;&#x5C0F;&#x9F20; VEGF C siRNA&#x3001; &#x53D1;&#x5C55;&#x3001; &#x589E;&#x957F;&#x548C;&#x5B9E;&#x9A8C;&#x7684;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x5F02;&#x4F4D;&#x75C7;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x4E86;&#x6BD4;&#x8F83;&#x4F53;&#x5185;&#x3002;&#x7ED3;&#x679C;&#x8868;&#x660E; VEGF-C &#x57FA;&#x56E0;&#x8868;&#x8FBE;&#x548C;&#x86CB;&#x767D;&#x8D28;&#x88AB;&#x589E;&#x52A0;&#x7684;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x5F02;&#x4F4D;&#x75C7;&#x60A3;&#x8005;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x3002;VEGF-C siRNA &#x663E;&#x8457;&#x6291;&#x5236;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x7EC6;&#x80DE;&#x8FC1;&#x79FB;&#x548C;&#x7BA1;&#x5F62;&#x6210;&#x3002;VEGF-C siRNA &#x5927;&#x5927;&#x963B;&#x788D;&#x4E86;&#x53D1;&#x5C55;&#x548C;&#x5B9E;&#x9A8C;&#x5C0F;&#x9F20;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x5F02;&#x4F4D;&#x75C5;&#x53D8;&#x7684;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x3002;&#x8865;&#x5145;&#x548C;&#x8FC7;&#x91CF;&#x8868;&#x8FBE; VEGF C &#x5927;&#x5927;&#x626D;&#x8F6C;&#x5BF9;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x529F;&#x80FD;&#x3001; &#x8840;&#x7BA1;&#x901A;&#x900F;&#x6027;&#x548C;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x5F02;&#x4F4D;&#x751F;&#x957F;&#x7684;&#x6291;&#x5236;&#x4F5C;&#x7528;&#x3002;&#x6700;&#x540E;&#xFF0C;&#x5728;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x589E;&#x52A0; VEGF-C&#xFF0C;&#x5B83;&#x4FC3;&#x8FDB;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x529F;&#x80FD;&#x3001; &#x8840;&#x7BA1;&#x901A;&#x900F;&#x6027;&#x548C;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x5F02;&#x4F4D;&#x75C7;&#x7684;&#x53D1;&#x5C55;&#x3002;VEGF C &#x662F;&#x91CD;&#x8981;&#x7684;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x7684;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x5F02;&#x4F4D;&#x75C7;&#x3002;

&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x751F;&#x957F;&#x56E0;&#x5B50; C &#x5728;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x589E;&#x52A0;&#xFF0C;&#x4FC3;&#x8FDB;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x529F;&#x80FD;&#x3001; &#x8840;&#x7BA1;&#x901A;&#x900F;&#x6027;&#x548C;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x548C;&#x589E;&#x957F;&#x7684;&#x5B50;&#x5BAB;&#x5185;&#x819C;&#x5F02;&#x4F4D;&#x75C7;&#x3002;

Endometriosis is an angiogenesis-dependent disease. Many studies demonstrated inhibition of angiogenesis leads to inhibition of endometriotic growth, however underlying mechanism is still not fully understood. Our previous study suggested vascular endothelial growth factor C (VEGF-C) as a target of anti-angiogenesis therapy for endometriosis. In this study, VEGF-C in endometrium and its role in angiogenesis of endometriosis were studied. Human endometrium were obtained from women with and without endometriosis for molecular studies. VEGF-A, VEGF-B, VEGF-C and VEGF-D mRNA and proteins in eutopic and ectopic endometrium were measured. Human endothelial cells were transfected with VEGF-C siRNA in vitro, effects of VEGF-C on endothelial cell migration, invasion and tube formation were investigated in vitro. Angiogenesis was inhibited in wild type mice, vascular permeability in dermal skin was determined in vivo. Transplanted endometrium were inhibited by VEGF-C siRNA in immunocompromised mice, development, growth and angiogenesis of the experimental endometriosis were compared in vivo. The results showed that VEGF-C mRNA and protein were increased in eutopic and ectopic endometrium of endometriosis patients. VEGF-C siRNA significantly inhibited endothelial cell migration and tube formation. VEGF-C siRNA significantly inhibited development and angiogenesis of the experimental endometriotic lesions in mice. Supplementation and over-expression of VEGF-C significantly reversed the inhibitory effects on the endothelial functions, vascular permeability and endometriotic growth. In conclusion, VEGF-C is increased in endometrium and it promotes endothelial functions, vascular permeability and development of experimental endometriosis. VEGF-C is important for angiogenesis in endometriosis.

Vascular endothelial growth factor C is increased in endometrium and promotes endothelial functions, vascular permeability and angiogenesis and growth of endometriosis.

L&#39;endom&eacute;triose est une maladie de l&#39;angiogen&egrave;se d&eacute;pendant. De nombreuses &eacute;tudes ont d&eacute;montr&eacute; l&#39;inhibition de l&#39;angiogen&egrave;se conduit &agrave; l&#39;inhibition de la croissance endometriotic, m&eacute;canisme sous-jacent mais n&#39;est toujours pas enti&egrave;rement comprise. Notre &eacute;tude pr&eacute;c&eacute;dente sugg&egrave;re vascular endothelial growth factor C (VEGF-C) comme cible de la th&eacute;rapie anti-angiogen&egrave;se pour endom&eacute;triose. Dans cette &eacute;tude, le VEGF-C dans l&#39;endom&egrave;tre et son r&ocirc;le dans l&#39;angiogen&egrave;se de l&#39;endom&eacute;triose ont &eacute;t&eacute; &eacute;tudi&eacute;s. L&#39;endom&egrave;tre humain proviennent de femmes avec et sans l&#39;endom&eacute;triose pour les &eacute;tudes mol&eacute;culaires. VEGF-A, VEGF-B, VEGF-C et VEGF-D ARNm et prot&eacute;ines eutopique et endom&egrave;tre ectopique ont &eacute;t&eacute; mesur&eacute;s. Les cellules endoth&eacute;liales humaines ont &eacute;t&eacute; transfect&eacute;es avec des siARN de VEGF-C in vitro, ont &eacute;tudi&eacute; les effets de VEGF-C sur la formation de tube, l&#39;invasion et la migration des cellules endoth&eacute;liales in vitro. L&#39;angiogen&egrave;se est inhib&eacute;e chez les souris de type sauvage, la perm&eacute;abilit&eacute; vasculaire dans la peau par voie cutan&eacute;e a &eacute;t&eacute; d&eacute;termin&eacute;e in vivo. Endom&egrave;tre transplant&eacute; ont &eacute;t&eacute; inhib&eacute;es par siARN VEGF-C chez des souris immunod&eacute;ficientes, d&eacute;veloppement, croissance et angiogen&egrave;se de l&#39;endom&eacute;triose exp&eacute;rimental ont &eacute;t&eacute; compar&eacute;es in vivo. Les r&eacute;sultats ont montr&eacute; que les ARNm de VEGF-C et de prot&eacute;ines sont augment&eacute;es dans eutopique et endom&egrave;tre ectopique des patients de l&#39;endom&eacute;triose. SiARN de VEGF-C significativement inhib&eacute;e formation migration et tube de cellules endoth&eacute;liales. SiARN de VEGF-C significativement inhib&eacute;e d&eacute;veloppement et angiogen&egrave;se des l&eacute;sions endometriotic exp&eacute;rimentales chez la souris. Suppl&eacute;mentation et &agrave; la surexpression du VEGF-C sensiblement renvers&eacute; les effets inhibiteurs sur les fonctions endoth&eacute;liales, la perm&eacute;abilit&eacute; vasculaire et la croissance endometriotic. En conclusion, le VEGF-C est augment&eacute;e dans l&#39;endom&egrave;tre et il favorise les fonctions endoth&eacute;liales, la perm&eacute;abilit&eacute; vasculaire et le d&eacute;veloppement de l&#39;endom&eacute;triose exp&eacute;rimentale. VEGF-C est important pour l&#39;angiogen&egrave;se dans l&#39;endom&eacute;triose.

Facteur de croissance endoth&eacute;lial vasculaire C est augment&eacute;e dans l&#39;endom&egrave;tre et favorise les fonctions endoth&eacute;liales, la perm&eacute;abilit&eacute; vasculaire et l&#39;angiogen&egrave;se et la croissance de l&#39;endom&eacute;triose.

Endometriose ist eine Krankheit, Angiogenese-abh&auml;ngigen. Viele Studien gezeigt, dass die Hemmung der Angiogenese f&uuml;hrt zur Hemmung der endometriotic Wachstum, jedoch zugrunde liegenden Mechanismus noch nicht vollst&auml;ndig verstanden wird. Unsere vorherige Studie vorgeschlagen vaskul&auml;ren endothelialen Wachstumsfaktor (VEGF-C) C als Ziel der Anti-Angiogenese Therapie f&uuml;r Endometriose. In dieser Studie wurden VEGF-C im Endometrium und seine Rolle bei der Angiogenese der Endometriose untersucht. Menschlichen Endometrium wurden von Frauen mit und ohne Endometriose f&uuml;r Molekulare Studien erhalten. VEGF-A, wurden VEGF-B, VEGF-C und VEGF-D-mRNA und Proteine in Eutopic und Ektope Geb&auml;rmutterschleimhaut gemessen. Menschliche Endothelzellen wurden die mit VEGF-C SiRNA in-vitro-transfected, Auswirkungen von VEGF-C auf endothelial Zelle Migration, Invasion und Rohr Bildung wurden in-vitro untersucht. Angiogenese Wildtyp-M&auml;usen gehemmt wurde, vaskul&auml;re Permeabilit&auml;t in dermal Haut wurde in-vivo bestimmt. Transplantierten Endometrium wurden durch VEGF-C SiRNA bei immungeschw&auml;chten M&auml;usen gehemmt, Entwicklung, Wachstum und Angiogenese des experimentellen Endometriose wurden in-vivo verglichen. Die Ergebnisse zeigten, dass VEGF-C-mRNA und Protein in Eutopic und ektopisches Endometrium der Endometriose Patienten verl&auml;ngert wurde. VEGF-C SiRNA hemmte deutlich endothelial Zelle Migration und Rohr-Formation. VEGF-C SiRNA gehemmt deutlich Entwicklung und Angiogenese der experimentellen endometriotic L&auml;sionen in den M&auml;usen. Erg&auml;nzung und &Uuml;berexpression des VEGF-C umgekehrt deutlich die hemmende Wirkung auf die endotheliale Funktionen, vaskul&auml;re Permeabilit&auml;t und endometriotic Wachstum. Abschlie&szlig;end VEGF-C steigt in der Geb&auml;rmutterschleimhaut und f&ouml;rdert endothelialen Funktionen, vaskul&auml;re Permeabilit&auml;t und Entwicklung der experimentellen Endometriose. VEGF-C ist wichtig f&uuml;r die Angiogenese in Endometriose.

Vaskul&auml;ren endothelialen Wachstumsfaktor C erh&ouml;ht sich im Endometrium und f&ouml;rdert endothelialen Funktionen, vaskul&auml;re Permeabilit&auml;t und Angiogenese und Wachstum der Endometriose.

L&#39;endometriosi &egrave; una malattia dell&#39;angiogenesi-dipendente. Molti studi hanno dimostrato che l&#39;inibizione dell&#39;angiogenesi porta alla inibizione della crescita endometriotic, meccanismo sottostante tuttavia &egrave; ancora non pienamente compresa. Il nostro studio precedente suggerito vascular endothelial growth factor C (VEGF-C) come un obiettivo della terapia anti-angiogenesi per endometriosi. In questo studio, sono stati studiati VEGF-C nell&#39;endometrio e il suo ruolo nell&#39;angiogenesi dell&#39;endometriosi. Endometrio umano sono stati ottenuti da donne con e senza endometriosi per studi molecolari. VEGF-A, VEGF-B, VEGF-C e VEGF-D mRNA e proteine in eutopic ed endometrio ectopico sono state misurate. Cellule endoteliali umane sono state transfected con VEGF-C siRNA in vitro, sono stati indagati gli effetti del VEGF-C su migrazione, invasione e tubo la formazione di cellule endoteliali in vitro. L&#39;angiogenesi &egrave; stata inibita nei topi wild type, permeabilit&agrave; vascolare nel derma della pelle &egrave; stato determinato in vivo. Endometrio trapiantato sono stati inibiti da VEGF-C siRNA in topi immunocompromessi, lo sviluppo, la crescita e l&#39;angiogenesi dell&#39;endometriosi sperimentale sono stato confrontato in vivo. I risultati hanno mostrato che VEGF-C mRNA e proteina sono stati aumentati in eutopic ed endometrio ectopico di pazienti l&#39;endometriosi. VEGF-C siRNA significativamente ha inibito la formazione di migrazione e tubo di cellule endoteliali. VEGF-C siRNA inibito significativamente lo sviluppo e l&#39;angiogenesi delle lesioni endometriotic sperimentale nei topi. Supplementazione e sovraespressione di VEGF-C invertito significativamente gli effetti inibitori sulle funzioni endoteliali, permeabilit&agrave; vascolare e crescita endometriotic. In conclusione, VEGF-C &egrave; aumentato nell&#39;endometrio e favorisce le funzioni endoteliali, permeabilit&agrave; vascolare e lo sviluppo dell&#39;endometriosi sperimentale. VEGF-C &egrave; importante per l&#39;angiogenesi in endometriosi.

Fattore di crescita endoteliale vascolare C &egrave; aumentato nell&#39;endometrio e favorisce le funzioni endoteliali, permeabilit&agrave; vascolare e angiogenesi e crescita dell&#39;endometriosi.

&#x5B50;&#x5BAE;&#x5185;&#x819C;&#x75C7;&#x306F;&#x3001;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x306B;&#x4F9D;&#x5B58;&#x3059;&#x308B;&#x75BE;&#x60A3;&#x3067;&#x3059;&#x3002;&#x591A;&#x304F;&#x306E;&#x7814;&#x7A76;&#x306F;&#x3001;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x306E;&#x963B;&#x5BB3;&#x306E;&#x3057;&#x304B;&#x3057;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x3092;&#x307E;&#x3060;&#x5B8C;&#x5168;&#x306B;&#x7406;&#x89E3;&#x72B6;&#x306E;&#x5185;&#x5BB9;&#x306E;&#x5897;&#x6B96;&#x6291;&#x5236;&#x306B;&#x3064;&#x306A;&#x304C;&#x308B;&#x5B9F;&#x8A3C;&#x3002;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x5897;&#x6B96;&#x56E0;&#x5B50; C (VEGF C) &#x306E;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x3068;&#x3057;&#x3066;&#x5B50;&#x5BAE;&#x5185;&#x819C;&#x75C7;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x6297;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x7642;&#x6CD5;&#x306E;&#x524D;&#x304C;&#x793A;&#x5506;&#x3002;&#x672C;&#x7814;&#x7A76;&#x3067;&#x306F;, VEGF-C &#x5B50;&#x5BAE;&#x5185;&#x819C;&#x3068;&#x5B50;&#x5BAE;&#x5185;&#x819C;&#x75C7;&#x306E;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x306B;&#x304A;&#x3051;&#x308B;&#x5F79;&#x5272;&#x3092;&#x691C;&#x8A0E;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x5B50;&#x5BAE;&#x3068;&#x5B50;&#x5BAE;&#x5185;&#x819C;&#x75C7;&#x5206;&#x5B50;&#x7814;&#x7A76;&#x306E;&#x305F;&#x3081;&#x306E;&#x5973;&#x6027;&#x304B;&#x3089;&#x5F97;&#x305F;&#x3002;VEGF &#x306F; VEGF B&#x3001;VEGF C &#x3068; VEGF D mRNA &#x304A;&#x3088;&#x3073;&#x86CB;&#x767D;&#x8CEA; eutopic &#x3068;&#x7570;&#x6240;&#x6027;&#x306E;&#x5B50;&#x5BAE;&#x5185;&#x819C;&#x3067;&#x6E2C;&#x5B9A;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x3072;&#x3068;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x7D30;&#x80DE;&#x3092; in vitro &#x3067;&#x306E; VEGF C siRNA &#x3092;&#x5C0E;&#x5165;&#x3055;&#x305B;&#x305F;&#x3001;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x7D30;&#x80DE;&#x306E;&#x79FB;&#x884C;&#x3001;&#x4FB5;&#x7565;&#x3001;&#x30C1;&#x30E5;&#x30FC;&#x30D6;&#x306E;&#x5F62;&#x6210;&#x306B;&#x53CA;&#x307C;&#x3059; VEGF C &#x306F; in vitro &#x3067;&#x691C;&#x8A0E;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x91CE;&#x751F;&#x578B;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x3092;&#x6291;&#x5236;&#x3057;&#x305F;&#x3001;&#x76AE;&#x819A;&#x306E;&#x76AE;&#x819A;&#x306E;&#x8840;&#x7BA1;&#x306E;&#x900F;&#x904E;&#x6027;&#x306F; in vivo &#x3067;&#x6C7A;&#x5B9A;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x79FB;&#x690D;&#x5B50;&#x5BAE;&#x5185;&#x819C;&#x514D;&#x75AB;&#x4E0D;&#x5168;&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B; VEGF C siRNA &#x306B;&#x3088;&#x3063;&#x3066;&#x6291;&#x5236;&#x3055;&#x308C;&#x305F;&#x3001;&#x958B;&#x767A;&#x3001;&#x6210;&#x9577;&#x3001;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x5B9F;&#x9A13;&#x7684;&#x5B50;&#x5BAE;&#x5185;&#x819C;&#x75C7;&#x306E; in vivo &#x3067;&#x6BD4;&#x8F03;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;VEGF C mRNA &#x304A;&#x3088;&#x3073;&#x86CB;&#x767D;&#x8CEA; eutopic &#x3068;&#x7570;&#x6240;&#x6027;&#x306E;&#x5B50;&#x5BAE;&#x5185;&#x819C;&#x306E;&#x5B50;&#x5BAE;&#x5185;&#x819C;&#x75C7;&#x60A3;&#x8005;&#x3067;&#x5897;&#x52A0;&#x3057;&#x305F;&#x3053;&#x3068;&#x304C;&#x793A;&#x5506;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;VEGF C siRNA &#x306F;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x7D30;&#x80DE;&#x306E;&#x79FB;&#x884C;&#x3068;&#x30C1;&#x30E5;&#x30FC;&#x30D6;&#x306E;&#x5F62;&#x6210;&#x3092;&#x6709;&#x610F;&#x306B;&#x6291;&#x5236;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;VEGF C siRNA &#x306F;&#x3001;&#x5927;&#x5E45;&#x306B;&#x958B;&#x767A;&#x3068;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x5B9F;&#x9A13;&#x7684;&#x72B6;&#x306E;&#x5185;&#x5BB9;&#x306E;&#x75C5;&#x5909;&#x306E;&#x6291;&#x5236;&#x3002;&#x88DC;&#x5145;&#x3068; VEGF C &#x306E;&#x904E;&#x5270;&#x767A;&#x73FE;&#x306E;&#x6291;&#x5236;&#x52B9;&#x679C;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x6A5F;&#x80FD;&#x3001;&#x8840;&#x7BA1;&#x900F;&#x904E;&#x6027;&#x3068;&#x72B6;&#x306E;&#x5185;&#x5BB9;&#x306E;&#x6210;&#x9577;&#x306B;&#x95A2;&#x3059;&#x308B;&#x9006;&#x306B;&#x5927;&#x5E45;&#x306B;&#x3002;&#x7D50;&#x8AD6;&#x3068;&#x3057;&#x3066;&#x306F;&#x3001;&#x5B50;&#x5BAE;&#x5185;&#x819C; VEGF C &#x304C;&#x5897;&#x52A0;&#x3057;&#x3001;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x6A5F;&#x80FD;&#x3001;&#x8840;&#x7BA1;&#x900F;&#x904E;&#x6027;&#x3068;&#x5B9F;&#x9A13;&#x7684;&#x5B50;&#x5BAE;&#x5185;&#x819C;&#x75C7;&#x306E;&#x958B;&#x767A;&#x3092;&#x63A8;&#x9032;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;VEGF C &#x306F;&#x5B50;&#x5BAE;&#x5185;&#x819C;&#x75C7;&#x306B;&#x304A;&#x3051;&#x308B;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x306E;&#x3053;&#x3068;&#x304C;&#x91CD;&#x8981;&#x3067;&#x3059;&#x3002;

&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x5897;&#x6B96;&#x56E0;&#x5B50; C &#x306F;&#x3001;&#x5B50;&#x5BAE;&#x5185;&#x819C;&#x304C;&#x5897;&#x52A0;&#x3057;&#x3001;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x6A5F;&#x80FD;&#x3001;&#x8840;&#x7BA1;&#x900F;&#x904E;&#x6027;&#x3068;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x3068;&#x5B50;&#x5BAE;&#x5185;&#x819C;&#x75C7;&#x306E;&#x6210;&#x9577;&#x3092;&#x4FC3;&#x9032;&#x3057;&#x307E;&#x3059;&#x3002;

&#xC790;&#xAD81;&#xB0B4; &#xB9C9; &#xC99D;&#xC740; &#xC2E0;&#xC0DD; &#xC885;&#xC18D; &#xC9C8;&#xBCD1; &#xC774;&#xB2E4;. &#xD558;&#xC9C0;&#xB9CC; &#xB9CE;&#xC740; &#xC5F0;&#xAD6C; &#xACB0;&#xACFC; &#xD608;&#xAD00; &#xC2E0;&#xC0DD;&#xC758; &#xC5B5;&#xC81C; &#xB9AC;&#xB4DC; &#xAE30;&#xBCF8; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC740; &#xC544;&#xC9C1; &#xC644;&#xC804;&#xD788; &#xC774;&#xD574; endometriotic &#xC131;&#xC7A5;&#xC758; &#xC800;&#xD574; &#xC2DC;&#xC5F0; &#xD588;&#xB2E4;. &#xC6B0;&#xB9AC;&#xC758; &#xC774;&#xC804; &#xC5F0;&#xAD6C;&#xB294; &#xD608;&#xAD00; &#xB0B4; &#xD53C; &#xC131;&#xC7A5; &#xC778;&#xC790; (VEGF C) &#xB300;&#xC0C1;&#xC73C;&#xB85C; C&#xC758; &#xAD81;&#xC5D0; &#xB300; &#xD55C; &#xC548;&#xD2F0;-&#xD608;&#xAD00; &#xC2E0;&#xC0DD; &#xCE58;&#xB8CC; &#xC81C;&#xC548; &#xD588;&#xB2E4;. &#xC774; &#xC5F0;&#xAD6C;&#xC5D0;&#xC11C; VEGF&#xC758; C endometrium&#xACFC; &#xC790;&#xAD81;&#xB0B4; &#xB9C9;&#xC758; &#xC2E0;&#xC0DD;&#xC758; &#xC5ED;&#xD560; &#xACF5;&#xBD80;&#xB97C; &#xD588;&#xB2E4;. &#xC778;&#xAC04;&#xC758; endometrium &#xC5EC;&#xC131; &#xBC0F; &#xBD84;&#xC790; &#xC5F0;&#xAD6C;&#xC5D0; &#xB300; &#xD55C; &#xAD81;&#xC5D0;&#xC11C;&#xC5D0;&#xC11C; &#xC785;&#xC218; &#xD588;&#xB2E4;. VEGF A VEGF-B, C VEGF&#xC640; VEGF &#xCC28;&#xC6D0; mRNA, eutopic &#xBC0F; &#xC18C;&#xC131; endometrium&#xC5D0; &#xB2E8;&#xBC31;&#xC9C8; &#xCE21;&#xC815; &#xB418;&#xC5C8;&#xB2E4;. &#xC778;&#xAC04;&#xC758; &#xB0B4; &#xD53C; &#xC138;&#xD3EC; &#xC0DD;&#xCCB4; &#xC678;&#xC5D0;&#xC11C; VEGF C Sirna&#xC640; &#xD398; &#xD588;&#xB2E4;, &#xB0B4; &#xD53C; &#xC138;&#xD3EC; &#xB9C8;&#xC774;&#xADF8;&#xB808;&#xC774;&#xC158;, &#xCE68;&#xB7B5;&#xACFC; &#xAD00; &#xD615;&#xC131;&#xC5D0; VEGF C&#xC758; &#xD6A8;&#xACFC; &#xCCB4; &#xC678; &#xC870;&#xC0AC; &#xD588;&#xB2E4;. &#xC57C;&#xC0DD; &#xD0C0;&#xC785; &#xB9C8;&#xC6B0;&#xC2A4;&#xC5D0; &#xC2E0;&#xC0DD;&#xC744; &#xC800;&#xD574;, &#xD53C;&#xBD80; &#xD53C;&#xBD80; &#xD608;&#xAD00; &#xCE68;&#xD22C;&#xC131; vivo&#xC5D0;&#xC11C; &#xACB0;&#xC815; &#xD588;&#xB2E4;. &#xC774;&#xC2DD;&#xB41C; endometrium immunocompromised &#xC0DD;&#xC950;&#xC5D0;&#xC11C; VEGF C Sirna&#xC5D0; &#xC758;&#xD574; &#xC800;&#xD574; &#xB418;&#xC5C8;&#xB2E4;, &#xAC1C;&#xBC1C;, &#xC131;&#xC7A5; &#xBC0F; &#xC2E4;&#xD5D8; &#xC790;&#xAD81;&#xB0B4; &#xB9C9;&#xC758; &#xC2E0;&#xC0DD; vivo&#xC5D0;&#xC11C; &#xBE44;&#xAD50; &#xD588;&#xB2E4;. &#xACB0;&#xACFC; VEGF C Mrna&#xC640; &#xB2E8;&#xBC31;&#xC9C8; eutopic &#xBC0F; &#xC18C;&#xC131; endometrium &#xC790;&#xAD81;&#xB0B4; &#xB9C9; &#xC99D; &#xD658;&#xC790;&#xC758; &#xC99D;&#xAC00; &#xD588;&#xB2E4; &#xBCF4;&#xC5EC;&#xC8FC;&#xC5C8;&#xB2E4;. VEGF C Sirna&#xB294; &#xD06C;&#xAC8C; &#xB0B4; &#xD53C; &#xC138;&#xD3EC; &#xB9C8;&#xC774;&#xADF8;&#xB808;&#xC774;&#xC158; &#xBC0F; &#xAD00; &#xD615;&#xC131;&#xC744; &#xC800;&#xD574;. VEGF C Sirna&#xB294; &#xD06C;&#xAC8C; &#xAC1C;&#xBC1C; &#xBC0F; &#xC950;&#xC5D0; &#xC788;&#xB294; &#xC2E4;&#xD5D8; endometriotic &#xBCC0;&#xC758; &#xC2E0;&#xC0DD; &#xC800;&#xD574;. &#xBCF4;&#xCDA9; &#xBC0F; VEGF C&#xC758; over-expression &#xB0B4; &#xD53C; &#xAE30;&#xB2A5;, &#xD608;&#xAD00; &#xCE68;&#xD22C;&#xC131; &#xBC0F; endometriotic &#xC131;&#xC7A5; &#xC5B5;&#xC81C; &#xD6A8;&#xACFC; &#xBC18;&#xB300;&#xB85C; &#xD06C;&#xAC8C;. &#xB05D;&#xC73C;&#xB85C;, VEGF C endometrium&#xC5D0; &#xC99D;&#xAC00; &#xD558; &#xACE0; &#xB0B4; &#xD53C; &#xAE30;&#xB2A5;&#xACFC; &#xD608;&#xAD00; &#xCE68;&#xD22C;&#xC131; &#xC2E4;&#xD5D8; &#xC790;&#xAD81;&#xB0B4; &#xB9C9;&#xC758; &#xBC1C;&#xB2EC;&#xC744; &#xCD09;&#xC9C4;. VEGF C &#xC2E0;&#xC0DD; &#xAD81;&#xC5D0;&#xC11C; &#xC911;&#xC694; &#xD558;&#xB2E4;.

&#xD608;&#xAD00; &#xB0B4; &#xD53C; &#xC131;&#xC7A5; &#xC778;&#xC790; C endometrium&#xC5D0; &#xC99D;&#xAC00; &#xD558; &#xACE0; &#xB0B4; &#xD53C; &#xAE30;&#xB2A5;, &#xD608;&#xAD00; &#xCE68;&#xD22C;&#xC131; &#xBC0F; &#xC2E0;&#xC0DD; &#xBC0F; &#xC790;&#xAD81;&#xB0B4; &#xB9C9;&#xC758; &#xC131;&#xC7A5;&#xC744; &#xCD09;&#xC9C4;.

La endometriosis es una enfermedad dependiente de la angiog&eacute;nesis. Muchos estudios demostraron que la inhibici&oacute;n de la angiog&eacute;nesis conduce a la inhibici&oacute;n de crecimiento endometri&oacute;sicos, mecanismo subyacente sin embargo no se entiende. Nuestro estudio anterior sugiri&oacute; vascular endothelial growth factor C (VEGF-C) como un objetivo de la terapia anti-angiog&eacute;nesis para la endometriosis. En este estudio, se estudiaron VEGF-C en el endometrio y su papel en la angiog&eacute;nesis de la endometriosis. Endometrio humano fueron obtenidos de mujeres con y sin endometriosis para estudios moleculares. VEGF-A, midieron VEGF-B, VEGF-C y D-VEGF mRNA y prote&iacute;nas en eutopic y endometrio ect&oacute;pico. C&eacute;lulas endoteliales humanas fueron transfectadas con VEGF-C siRNA in vitro, se investigaron efectos de VEGF-C sobre migraci&oacute;n, invasi&oacute;n y tubo la formaci&oacute;n de c&eacute;lulas endoteliales in vitro. Angiog&eacute;nesis se inhibi&oacute; en ratones de tipo salvaje, permeabilidad vascular en piel cut&aacute;nea se determin&oacute; in vivo. Endometrio trasplantado fueron inhibidos por VEGF-C siRNA en ratones inmunodeprimidos, desarrollo, crecimiento y angiog&eacute;nesis de la endometriosis experimental se compararon in vivo. Los resultados mostraron que el VEGF-C mRNA y prote&iacute;na se incrementaron en eutopic y endometrio ect&oacute;pico de pacientes de endometriosis. VEGF-C siRNA inhibieron significativamente la formaci&oacute;n de c&eacute;lulas endoteliales migraci&oacute;n y tubo. VEGF-C siRNA inhibieron significativamente el desarrollo y la angiog&eacute;nesis de las lesiones endometri&oacute;sicos experimentales en ratones. Suplementaci&oacute;n y sobreexpresi&oacute;n de VEGF-C invierten significativamente los efectos inhibitorios sobre las funciones endoteliales, la permeabilidad vascular y el crecimiento endometri&oacute;sicos. En conclusi&oacute;n, VEGF-C se incrementa en el endometrio y promueve funciones endoteliales, la permeabilidad vascular y el desarrollo de la endometriosis experimental. VEGF-C es importante para la angiog&eacute;nesis en endometriosis.

Factor de crecimiento endotelial vascular C es mayor en el endometrio y promueve funciones endoteliales, permeabilidad vascular y angiog&eacute;nesis y crecimiento de la endometriosis.

We have observed substantial differences in angiogenic responsiveness in mice and have mapped the genetic loci responsible for these differences. We have found that the albino mutation is one of the loci responsible for such differences. Using B6.A consomic strains, we determined that chromosome 7 bears a locus that inhibits VEGF-induced corneal neovascularization. F2 crosses between B6.A<Chromosome 7> consomic mice and C57BL/6J parents along with AXB and BXA recombinant inbred strains demonstrated highest linkage near the tyrosinase gene. This region was named AngVq4. Congenic animals confirmed this locus, but could not demonstrate that the classical tyrosinase albino (c) mutation was causative because of the existence of additional linked loci in the congenic region. However, in 1970, a second tyrosinase albino mutation (c-2J) arose in the C57BL/6J background at Jackson Labs. Testing this strain (C57BL/6J<c-2J>) demonstrated that the albino mutation is sufficient to completely explain the alteration in angiogenic response that we observed in congenic animals. Thus, we conclude that the classical tyrosinase mutation is responsible for AngVq4. In contrast to the cornea, where pigmented animals exhibit increased angiogenic responsiveness, iris neovascularization was inhibited in pigmented animals. These results may partially explain increased aggressiveness in amelanotic melanoma, as well as ethnic differences in diabetic retinopathy and macular degeneration.

The albino mutation of tyrosinase alters ocular angiogenic responsiveness.

Nous ont observ&eacute; des diff&eacute;rences substantielles angiog&eacute;nique r&eacute;activit&eacute; chez les souris et ont cartographi&eacute; les loci g&eacute;n&eacute;tiques responsables de ces diff&eacute;rences. Nous avons trouv&eacute; que la mutation albinos est l&#39;un des locus responsables de ces diff&eacute;rences. &Agrave; l&#39;aide de B6.Une tendance des souches, nous avons d&eacute;termin&eacute; que le chromosome 7 porte un locus qui inhibe la n&eacute;ovascularisation corn&eacute;enne induite par le VEGF. F2 de croisements entre B6.Un &lt; Chromosome 7 &gt; toutes souris et C57BL/6J parents avec recombinant AXB et BXA consanguines lien plu d&eacute;montr&eacute;e de souches pr&egrave;s du g&egrave;ne de la tyrosinase. Cette r&eacute;gion s&#39;appelait AngVq4. Animaux cong&eacute;niques a confirm&eacute; ce locus, mais n&#39;a pu d&eacute;montrer que la mutation albinos (c) de la tyrosinase classique &eacute;tait responsable en raison de l&#39;existence d&#39;autres loci li&eacute;s dans la r&eacute;gion de cong&eacute;niques. Cependant, en 1970, une seconde mutation albinos de la tyrosinase (c-2J) s&#39;est pos&eacute;e dans le fond de C57BL/6J &agrave; Jackson Labs. Essais de cette souche (C57BL/6J &lt;c-2J&gt;) ont montr&eacute; que la mutation albinos suffit d&#39;expliquer compl&egrave;tement l&#39;alt&eacute;ration en r&eacute;ponse angiog&eacute;nique que nous avons observ&eacute; chez les animaux cong&eacute;niques. Par cons&eacute;quent, nous concluons que la mutation de la tyrosinase classique est responsable de la AngVq4. Contrairement &agrave; la corn&eacute;e, o&ugrave; les animaux pigment&eacute;s pi&egrave;ce r&eacute;activit&eacute; accrue angiog&eacute;nique, iris n&eacute;ovascularisation est inhib&eacute;e chez les animaux pigment&eacute;s. Ces r&eacute;sultats peuvent expliquer en partie une agressivit&eacute; accrue dans le M&eacute;lanome am&eacute;lanotique, ainsi que les diff&eacute;rences ethniques dans la r&eacute;tinopathie diab&eacute;tique et la d&eacute;g&eacute;n&eacute;rescence maculaire.

La mutation albinos de la tyrosinase modifie la r&eacute;activit&eacute; angiog&eacute;nique oculaire.

Ci sono osservate notevoli differenze in angiogenic reattivit&agrave; nei topi e hanno mappato i loci genetici responsabili di queste differenze. Abbiamo trovato che la mutazione albino &egrave; uno dei loci responsabili di tali differenze. Utilizzo di B6.Un consomic ceppi, abbiamo determinato che cromosoma 7 reca un locus che inibisce la neovascolarizzazione corneale indotta da VEGF. F2 attraversa tra B6.Un &lt; cromosoma 7 &amp;gt; C57BL/6J genitori insieme AXB e BXA ricombinante e consomic topi inbred dimostrata sollevatore pi&ugrave; ceppi vicino al gene della tirosinasi. Questa regione &egrave; stata denominata AngVq4. Animali congenici confermato questo locus, ma non potrebbero dimostrare che la mutazione albino (c) tirosinasi classica era causa a causa dell&#39;esistenza di ulteriori loci collegati nella regione congenici. Tuttavia, nel 1970, una seconda mutazione albino di tirosinasi (c-2J) &egrave; sorto in background C57BL/6J Jackson Labs. Prova questo ceppo (C57BL/6J &lt;c-2J&gt;) hanno dimostrato che la mutazione albino &egrave; sufficiente a spiegare completamente l&#39;alterazione nella risposta angiogenic che abbiamo osservato in animali congenici. Cos&igrave;, concludiamo che la mutazione di tirosinasi classica &egrave; responsabile AngVq4. In contrasto con la cornea, dove gli animali pigmentati esibiscono angiogenic maggiore reattivit&agrave;, iris neovascolarizzazione &egrave; stato inibito in animali pigmentati. Questi risultati possono spiegare parzialmente aumento dell&#39;aggressivit&agrave; nel melanoma amelanotico, cos&igrave; come le differenze etniche nella retinopatia diabetica e la degenerazione maculare.

La mutazione albino di tirosinasi altera la risposta angiogenic oculare.

Studies have established that pigmentation can provide strong, protective effects against certain human diseases. For example, angiogenesis-dependent diseases such as wet age-related macular degeneration and infantile hemangioma are more common in light-skinned individuals of mixed European descent than in African-Americans. Here we found that melanocytes from light-skinned humans and albino mice secrete high levels of fibromodulin (FMOD), which we determined to be a potent angiogenic factor. FMOD treatment stimulated angiogenesis in numerous in vivo systems, including laser-induced choroidal neovascularization, growth factor-induced corneal neovascularization, wound healing, and Matrigel plug assays. Additionally, FMOD enhanced vascular sprouting during normal retinal development. Deletion of Fmod in albino mice resulted in a marked reduction in the amount of neovascularization induced by retinal vein occlusion, corneal growth factor pellets, and Matrigel plugs. Our data implicate the melanocyte-secreted factor FMOD as a key regulator of angiogenesis and suggest an underlying mechanism for epidemiological differences between light-skinned individuals of mixed European descent and African-Americans. Furthermore, inhibition of FMOD in humans has potential as a therapeutic strategy for treating angiogenesis-dependent diseases.

Article	Year
S-3-Amino-phthalimido-glutarimide inhibits angiogenesis and growth of B-cell neoplasias in mice. Cancer research\| PubMed ID: 11956087	2002
Genetic loci that control vascular endothelial growth factor-induced angiogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology\| PubMed ID: 12958152	2003
Genetic loci that control the angiogenic response to basic fibroblast growth factor. FASEB journal : official publication of the Federation of American Societies for Experimental Biology\| PubMed ID: 15226265	2004
A 27-amino-acid synthetic peptide corresponding to the NH2-terminal zinc-binding domain of endostatin is responsible for its antitumor activity. Cancer research\| PubMed ID: 15867360	2005
Antiangiogenic effect of oral 2-methoxyestradiol on choroidal neovascularization in mice. Experimental eye research\| PubMed ID: 16828472	2006
Chronic suppression of angiogenesis following radiation exposure is independent of hematopoietic reconstitution. Cancer research\| PubMed ID: 17332332	2007
Mutant anthrax toxin B moiety (protective antigen) inhibits angiogenesis and tumor growth. Cancer research\| PubMed ID: 17942931	2007
The mouse cornea micropocket angiogenesis assay. Nature protocols\| PubMed ID: 17947997	2007
Differential suppression of vascular permeability and corneal angiogenesis by nonsteroidal anti-inflammatory drugs. Investigative ophthalmology & visual science\| PubMed ID: 18487370	2008
Genetic loci that control the size of laser-induced choroidal neovascularization. FASEB journal : official publication of the Federation of American Societies for Experimental Biology\| PubMed ID: 19237505	2009
Green tea epigallocatechin-3-gallate inhibits angiogenesis and suppresses vascular endothelial growth factor C/vascular endothelial growth factor receptor 2 expression and signaling in exper... Fertility and sterility\| PubMed ID: 21821246	2011
The classical pink-eyed dilution mutation affects angiogenic responsiveness. PloS one\| PubMed ID: 22615734	2012
Endostatin lowers blood pressure via nitric oxide and prevents hypertension associated with VEGF inhibition. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 22733742	2012
Vascular endothelial growth factor C is increased in endometrium and promotes endothelial functions, vascular permeability and angiogenesis and growth of endometriosis. Angiogenesis\| PubMed ID: 23334337	2013
The albino mutation of tyrosinase alters ocular angiogenic responsiveness. Angiogenesis\| PubMed ID: 23423728	2013
Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment. The Journal of clinical investigation\| PubMed ID: 24355922	2014

Amy E. Birsner

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