Endothelial cells that form the inner layers of both blood and lymphatic vessels are important components of the vascular system and are involved in the pathogenesis of vascular and lymphatic diseases. Angiopoietin (Ang)-Tie axis in endothelial cells is the second endothelium-specific ligand-receptor signaling system necessary for embryonic cardiovascular and lymphatic development in addition to the vascular endothelial growth factor receptor pathway. The Ang-Tie axis also maintains vascular homeostasis by regulating postnatal angiogenesis, vessel remodeling, vascular permeability, and inflammation. Therefore, the dysfunction of this system leads to many vascular and lymphatic diseases. In light of the recent advances on the role of the Ang-Tie axis in vascular and lymphatic system-related diseases, this review summarizes the functions of the Ang-Tie axis in inflammation-induced vascular permeability, vascular remodeling, ocular angiogenesis, shear stress response, atherosclerosis, tumor angiogenesis, and metastasis. Moreover, this review summarizes the relevant therapeutic antibodies, recombinant proteins, and small molecular drugs associated with the Ang-Tie axis.
Angiopoietins ; Endothelial Cells/metabolism* ; Humans ; Lymphatic Diseases ; Lymphatic System/metabolism* ; Receptor, TIE-2/metabolism* ; Signal Transduction ; Vascular Endothelial Growth Factor A

Angiogenesis is a crucial process in the development of inflammatory diseases, including cancer, psoriasis and rheumatoid arthritis. Recently, several alkaloids from Picrasma quassioides had been screened for angiogenic activity in the zebrafish model, and the results indicated that 1-methoxycarbony-β-carboline (MCC) could effectively inhibit blood vessel formation. In this study, we further confirmed that MCC can inhibit, in a concentration-dependent manner, the viability, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro, as well as the regenerative vascular outgrowth of zebrafish caudal fin in vivo. In the zebrafish xenograft assay, MCC inhibited the growth of tumor masses and the metastatic transplanted DU145 tumor cells. The proteome profile array of the MCC-treated HUVECs showed that MCC could down-regulate several angiogenesis-related self-secreted proteins, including ANG, EGF, bFGF, GRO, IGF-1, PLG and MMP-1. In addition, the expression of two key membrane receptor proteins in angiogenesis, TIE-2 and uPAR, were also down-regulated after MCC treatment. Taken together, these results shed light on the potential therapeutic application of MCC as a potent natural angiogenesis inhibitor via multiple molecular targets.
Angiogenesis Inhibitors ; chemistry ; pharmacology ; Animals ; Carbolines ; chemistry ; pharmacology ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Epidermal Growth Factor ; genetics ; metabolism ; Fibroblast Growth Factors ; genetics ; metabolism ; Human Umbilical Vein Endothelial Cells ; cytology ; drug effects ; metabolism ; Humans ; Insulin-Like Growth Factor I ; genetics ; metabolism ; Neovascularization, Physiologic ; drug effects ; Picrasma ; chemistry ; Plant Extracts ; chemistry ; pharmacology ; Receptor, TIE-2 ; genetics ; metabolism ; Zebrafish ; embryology

In order to investigate the promoting effect of low-intensity treadmill exercise on rat dorsal wound healing and the mechanism, 20 Sprague-Dawley rats were randomly divided into two groups: exercise group (Ex) and non-exercise group (non-ex). The rats in Ex group were given treadmill exercise for one month, and those in non-ex group raised on the same conditions without treadmill exercise. Both groups received dorsal wound operation with free access to food and water. By two-week continuous observation and recording of the wound area, the healing rate was analyzed. The blood sample was collected at day 14 post-operation via cardiac puncture for determination of the number of endothelial progenitor cells (EPCs) by flow cytometry, and the concentrations of relevant cytokines such as basic fibroblast growth factor (bFGF), endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) were measured by ELISA. The skin tissue around the wound was dissected to observe the vascular density under the microscope after HE staining, to detect the mRNA level of VEGFR2 and angiopoietin-1 (Ang-1) receptor using RT-qPCR, and protein expression of a-smooth muscle actin (αSMA) and type III collagen (ColIII) using Western blotting. It was found that the wound area in Ex group was smaller at the same time point than in non-ex group. The number of circulating EPCs was greater and the concentrations of vasoactive factors such as VEGF, eNOS and bFGF were higher in Ex group than in non-ex group. HE staining displayed a higher vessel density in Ex group than in non-ex group. Moreover, the mRNA expression of VEGFR2 and Ang-1 detected in the wound tissue in Ex group was higher than in non-ex group. Meanwhile, the protein expression of αSMA and ColIII was more abundant in Ex group than in non-ex group. Conclusively, the above results demonstrate Ex rats had a higher wound healing rate, suggesting low-intensity treadmill exercise accelerates wound healing. The present work may provide some hint for future study of treating refractory wound.
Actins ; metabolism ; Animals ; Collagen Type III ; metabolism ; Cytokines ; blood ; Endothelial Progenitor Cells ; cytology ; Male ; Nitric Oxide Synthase Type III ; blood ; Physical Exertion ; RNA, Messenger ; blood ; Rats ; Rats, Sprague-Dawley ; Receptor, TIE-1 ; metabolism ; Running ; Vascular Endothelial Growth Factor A ; blood ; Vascular Endothelial Growth Factor Receptor-2 ; blood ; Wound Healing

The tyrosine kinase system angiopoietin (Ang)/Tie interacts with vascular endothelial growth factor pathway and regulates vessel quiescence in adults as well as later steps of the angiogenic cascade related to vessel maturation. Since all Angs are able to bind to Tie-2 but none binds to Tie-1, the function of Tie-2 and its ligands have captured attention. However, emerging evidence indicates unique roles of the orphan receptor Tie-1 in angiogenesis under physiological and pathological conditions. It is required for maintaining vascular endothelial cell integrity and survival during murine embryo development and in adult and may be involved in modulating differentiation of hematopoietic cells in adult. Tie-1 exhibits poor tyrosine kinase activity and signals via forming heterodimers with Tie-2, inhibiting Tie-2 signaling mediated by Angs. This inhibition can be relieved by Tie-1 ectodomain cleavage mediated by tumor- and inflammatory-related factors, which causes destabilization of vessels and initiates vessel remodeling. Up-regulated Tie-1 expression has been found not only in some leukemia cells and tumor related endothelial cells but also in cytoplasm of carcinoma cells of a variety of human solid tumors, which is associated with tumor progression. In addition, it has pro-inflammatory functions in endothelial cells and is involved in some inflammatory diseases associated with angiogenesis. Recent research indicated that Tie-1 gene ablation exhibited significant effects on tumor blood- and lymph-angiogenesis and improved anti-Ang therapy, suggesting Tie-1 may be a potential target for tumor anti-angiogenesis treatment.
Angiogenesis Inhibitors ; therapeutic use ; Angiopoietins ; genetics ; metabolism ; Animals ; Embryo, Mammalian ; Embryonic Development ; genetics ; Endothelial Cells ; drug effects ; metabolism ; pathology ; Gene Expression Regulation, Developmental ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; Neovascularization, Pathologic ; drug therapy ; genetics ; metabolism ; pathology ; Protein Binding ; Receptor, TIE-1 ; antagonists & inhibitors ; genetics ; metabolism ; Receptor, TIE-2 ; genetics ; metabolism ; Signal Transduction

Psoriasis is a chronic inflammatory disease related to genome-wide and surroundings, it is important to develop a suitable animal model to research psoriasis pathogenesis and evolve pharmacotherapeutics. With the development of transgenetic technology in the past few years, psoriasis virulence gene animal model become a hotspot. Research of animal model of human psoriasis genes is reviewed in the paper.
Aminoquinolines ; toxicity ; Amphiregulin ; Animals ; Disease Models, Animal ; EGF Family of Proteins ; genetics ; metabolism ; Humans ; Keratin-14 ; genetics ; metabolism ; Keratin-5 ; genetics ; metabolism ; Keratinocytes ; metabolism ; Membrane Glycoproteins ; agonists ; Mice, Transgenic ; Psoriasis ; etiology ; genetics ; metabolism ; Receptor, TIE-2 ; genetics ; metabolism ; STAT3 Transcription Factor ; genetics ; metabolism ; Toll-Like Receptor 7 ; agonists ; Transforming Growth Factor beta1 ; genetics ; metabolism

OBJECTIVETo observe the effect of Taohong Siwu decoction (THSWD) on micro-vascular density (MVD) in rat uterus, the content of angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) in serum, and the expression of tyrosine kinasa receptor (Tie-2) in uterus.

METHODEarly pregnancy rats were intragastrically administrated with misoprostol (100 microg x kg(-1)) and mifepristong (8.3 mg x kg(-1)) to established the incomplete-abortion model. The incomplete-abortion rats were randomly divided into the model group (the same volume of distilled water), the positive control group (at the daily dose of 4.3 g x kg(-1) Motherwort Particles), and THSWD-treated groups (at the daily dose of 18.0, 9.0 and 4.5 g x kg(-1)). Pregnant rats were taken as the control group (the same volume of distilled water). After the successive oral administration for 7 days, blood was collected from aorta abdominalis, and rat uterine tissues were collected. The content of serum Ang-1 and Ang-2 were detected by ELISA; And the levels of Tie-2 and MVD in uterine tissues were detected by SP immunohistochemistry.

RESULTTHSWD remarkably increased the levels of MVD in uterus of medicine-induced abortion rats, the content of Ang-1 and Ang-2 in serum, and the expression of Tie-2 in uterine tissues.

CONCLUSIONTHSWD has the effect in markedly promoting angiogenesis in incomplete-abortion rats. Its mechanism may be related to the regulation of concentrations of Ang-1 and Ang-2 in serum and Tie-2 in uterine tissues.

Abortion, Incomplete ; blood ; drug therapy ; genetics ; Angiopoietin-1 ; blood ; genetics ; Angiopoietin-2 ; blood ; genetics ; Animals ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Gene Expression ; drug effects ; Humans ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Receptor, TIE-2 ; genetics ; metabolism ; Uterus ; blood supply ; drug effects ; metabolism

OBJECTIVETo study the expression of angiotensin-2 (Ang-2), Tie-2 and vascular endothelial growth factor receptor-2 (VEGFR-2) in colorectal cancer and analyze their relationship with the occurrence, recurrence, metastasis, angiogenesis and prognosis of colorectal cancer.

METHODSImmunohistochemistry with SP method was used to detect the expressions of Ang-2, Tie-2 and VEGFR-2 in 118 colorectal cancer, 40 adjacent normal tissue and 40 benign colorectal lesion specimens.

RESULTSThe positivity rates of Ang-2, Tie-2 and VEGFR-2 in colorectal cancer tissue were 74.58%, 69.49%, and 61.02%, respectively, significantly higher than those in the adjacent normal tissues (25.00%, 17.50%, and 17.50%, P<0.05) and benign colorectal lesion tissues (35.00%, 32.50%, and 32.50%, P<0.05). The rates of two or three coexpression were significantly higher than that of a single expression in the cancer tissues (61.02% vs 15.25%). The microvascular density (MVD) of colorectal cancer tissues was 31.43∓10.50, significantly higher than that of the adjacent normal tissues (10.61∓3.76) and benign colorectal lesions (16.89∓3.83) (P<0.05). The expressions of Ang-2, Tie-2, and VEGFR-2 were positively correlated with carcinoembryonic antigen (CEA) and MVD (P<0.05). The expression of Ang-2, but not Tie-2 and VEGFR-2, was positively correlated with CA199. Ang-2, Tie-2, and VEGFR-2 expressions showed significant differences between cases with tumor recurrence/metastasis and those without 5 years after radical mastectomy, and were all positively correlated with the 5-year survival rates (P<0.05).

CONCLUSIONAng-2, Tie-2 and VEGFR-2 are involved in the development, invasion, metastasis, and prognosis of colorectal cancer, and play important roles in the angiogenesis of the tumors.

Adolescent ; Adult ; Aged ; Angiopoietin-2 ; metabolism ; Colorectal Neoplasms ; blood supply ; metabolism ; Female ; Humans ; Male ; Middle Aged ; Neovascularization, Pathologic ; metabolism ; Prognosis ; Receptor, TIE-2 ; metabolism ; Vascular Endothelial Growth Factor Receptor-2 ; metabolism ; Young Adult

Angiopoietins ; metabolism ; physiology ; Animals ; Cell Proliferation ; Endothelial Cells ; cytology ; physiology ; Humans ; Neoplasms ; blood supply ; Neovascularization, Pathologic ; physiopathology ; Neovascularization, Physiologic ; physiology ; Pericytes ; cytology ; metabolism ; physiology ; Proto-Oncogene Proteins c-sis ; metabolism ; physiology ; Receptor, Platelet-Derived Growth Factor beta ; metabolism ; physiology ; Receptor, TIE-2 ; metabolism ; physiology ; Signal Transduction

OBJECTIVETo study the expression of angiopoietin-1 (Ang-1) and its receptor Tie-2 in multiple myeloma (MM) patients and RPMI8226 cells, and analyze the significance of Ang-1 expression and its relevance to the tumorigenes and development of MM.

METHODSRT-PCR and Western blot were used to detect the expression of Ang-1 and Tie-2 in bone marrow (BM) samples from 112 MM patients and 24 control subjects, and in RPMI8226 cells. The expression levels of Ang-1 in different groups and disease stages were analyzed.

RESULTSThe positive rate and expression level of Ang-1 were significantly higher in MM group than in control group (P < 0.05). The positive rates of Ang-1 were not significantly different between newly diagnosed and relapsed/refractory MM groups, but its expression level was significantly higher in the latter group than in the former group (P < 0.05). Tie-2 was detected only in 12 MM patients and did not in control group and RPMI8226 cells. Microvessel density in BM samples were significantly higher in MM group than in control group (25.21 ± 0.80 vs 5.23 ± 0.20, P < 0.01), and were higher in Ang-1-positive MM group than in Ang-1-negative MM group (32.98 ± 1.70 vs 16.55 ± 1.30, P < 0.05). The positive rates of Ang-1 protein were not significantly different between stage II and stage III MM (52.1% vs 60.9%, P > 0.05), but the expression level of Ang-1 protein was higher in stage III than that in stage II MM (0.40 ± 0.07 vs 0.22 ± 0.04, P < 0.05). In the newly diagnosed MM patients, the positive rate of Ang-1 protein in PD patients was significantly higher than in PR and MR patients (70.0% vs 19.1%, P < 0.01).

CONCLUSIONHigh expression of Ang-1 is found in MM patients and RPMI8226 cells, and its expression is associated with the disease stage, prognosis and targeted therapy of MM.

Angiopoietin-1 ; Humans ; Multiple Myeloma ; metabolism ; Prognosis ; RNA, Messenger ; Receptor, TIE-2

Angiopoietin-1 (Ang1) binds to and activates Tie2 receptor tyrosine kinase. Ang1-Tie2 signal has been proposed to exhibit two opposite roles in the controlling blood vessels. One is vascular stabilization and the other is vascular angiogenesis. There has been no answer to the question as to how Tie2 induces two opposite responses to the same ligand. Our group and Dr. Alitalo's group have demonstrated that trans-associated Tie2 at cell-cell contacts and extracellular matrix (ECM)-anchored Tie2 play distinct roles in the endothelial cells. The complex formation depends on the presence or absence of cell-cell adhesion. Here, we review how Ang1-Tie2 signal regulates vascular maintenance and angiogenesis. We further point to the unanswered questions that must be clarified to extend our knowledge of vascular biology and to progress basic knowledge to the treatment of the diseases in which Ang1-Tie2-mediated signal is central.
Angiopoietin-1/*physiology ; Animals ; Cell Adhesion/physiology ; Cell Movement/physiology ; Endothelial Cells/*physiology ; Endothelium, Vascular/physiology ; Extracellular Matrix/*metabolism ; Humans ; Neovascularization, Physiologic/physiology ; Receptor, TIE-2/*physiology ; Signal Transduction/*physiology