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PubMed1998

Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth.

An endothelial cell inhibitor was purified from supernatant of an Epstein-Barr virus-immortalized cell line and identified as fragments of calreticulin. The purified recombinant NH2-terminal domain of calreticulin (amino acids 1-180) inhibited the proliferation of endothelial cells, but not cells of other lineages, and suppressed angiogenesis in vivo. We have named this NH2-terminal domain of calreticulin vasostatin. When inoculated into athymic mice, vasostatin significantly reduced growth of human Burkitt lymphoma and human colon carcinoma. Compared with other inhibitors of angiogenesis, vasostatin is a small, soluble, and stable molecule that is easy to produce and deliver. As an angiogenesis inhibitor that specifically targets proliferating endothelial cells, vasostatin has a unique potential for cancer treatment.

Animals↗
PubMed2003

Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D.

Vascular endothelial growth factor (VEGF) C and VEGF-D stimulate lymphangiogenesis and angiogenesis in tissues and tumors by activating the endothelial cell surface receptor tyrosine kinases VEGF receptor (VEGFR) 2 and VEGFR-3. These growth factors are secreted as full-length inactive forms consisting of NH2- and COOH-terminal propeptides and a central VEGF homology domain (VHD) containing receptor binding sites. Proteolytic cleavage removes the propeptides to generate mature forms, consisting of dimers of the VEGF homology domain, that bind receptors with much greater affinity than the full-length forms. Therefore, proteolytic processing activates VEGF-C and VEGF-D, although the proteases involved were unknown. Here, we report that the serine protease plasmin cleaved both propeptides from the VEGF homology domain of human VEGF-D and thereby generated a mature form exhibiting greatly enhanced binding and cross-linking of VEGFR-2 and VEGFR-3 in comparison to full-length material. Plasmin also activated VEGF-C. As lymphangiogenic growth factors promote the metastatic spread of cancer via the lymphatics, the proteolytic activation of these molecules represents a potential target for antimetastatic agents. Identification of an enzyme that activates the lymphangiogenic growth factors will facilitate development of inhibitors of metastasis.

Animals↗
PubMed2003

Transit time kinetics in ordered and disordered vascular trees.

Imaging modalities exploit tracer-dilution methods to measure bulk haemodynamic parameters such as blood flow and volume at the level of the microcirculation. Here, we ask the question of whether the kinetics of a tracer can reveal morphological information about the vessels through which the tracers flow. The goal is to relate the acquired time-intensity characteristic to details of the vascular structure that lies below the imaging resolution. Two fractal vascular models are developed that represent organized 'kidney-like' and disorganized 'tumour-like' structures. The models are generated using simple rules of branching and fractal geometry in two dimensions. Blood flow and tracer kinetics are simulated using fundamental laws of haemodynamics. The flow conditions are matched in the two models. The fractal box dimensions of the kidney (D(B) = 1.67 +/- 0.01) and the tumour (D(B) = 1.80 +/- 0.01) vasculatures fall in the range given in the literature (D(B) = 1.61 +/- 0.06 and D(B) = 1.84 +/- 0.04, respectively). The tracer kinetic curves of the kidney and the tumour vasculatures have the same initial slope and final asymptote, corresponding to the same flow rate and vascular volume, but have different forms. The difference in the two curves is related to the distribution function of transit times of the vascular models, and is a consequence of the randomness introduced in vessel diameter and length. In principle, the form of the tracer kinetic curve from a contrast imaging study may offer information relating not only to vascular volume and flow rate, but also to the organization of a microvascular network.

Algorithms↗
PubMed2001

Inhibition of tumor growth and metastasis by Korean mistletoe lectin is associated with apoptosis and antiangiogenesis.

The mistletoe lectins are major active components in the extract of European mistletoes that have been widely used in adjuvant chemotherapy of cancer. This study was performed to investigate the mechanism of anticancer and antimetastatic activity of the purified Korean mistletoe lectin (Viscum album L. coloratum agglutinin, VCA). C57BL6 mice inoculated with B16-BL6 melanoma cells and treated with VCA were assessed for survival and metastasis. The induction of apoptosis of B16-BL6 cells by VCA was investigated by morphological changes, DNA fragmentation characteristics, and cell cycle analysis. The antiangiogenic activity of VCA was also measured by the CAM (choriallantoic membrane) assay. Length of survival of mice was increased and lung metastasis was inhibited by VCA. Treatment of cells with VCA resulted in growth suppression, nuclear morphological changes, DNA fragmentation, and an increased fraction of cells in sub-G1 consistent with apoptosis. Antiangiogenesis of VCA was assessed by CAM assay, where vessel growth induced by fat emulsion was decreased. These results suggest that VCA inhibits tumor growth and metastasis by increasing apoptosis and inhibiting angiogenesis.

Allantois↗
PubMed2003

Development of targeted somatostatin-based antiangiogenic therapy: a review and future perspectives.

Angiogenesis, the development of new blood vessels, is a critical determinant of tumor growth and the dissemination of metastasis. A number of antiangiogenic therapies have been introduced into clinical trials, though few of these are targeted therapies. Somatostatin analogs may be an excellent candidate to develop as targeted antiangiogenic agents alone, or in combination with cytotoxic or cytostatic compounds. Somatostatin analog inhibition of angiogenesis has been demonstrated in the chicken chorioallantoic membrane (CAM) model, the human umbilical vein endothelial cell (HUVEC) proliferation model, and the human placental vein angiogenesis model (HPVAM). This inhibition appears to be the result of a unique upregulation of somatostatin receptor subtype 2 (sst 2) during the angiogenic switch from resting to proliferating endothelium. The distinct overexpression of this receptor provides a unique target for these somatostatin analogs or somatostatin analog conjugates. This manuscript reviews the development of somatostatin analogs as antiangiogenics in both their unlabeled and radiolabeled forms and postulates on future developments in this field.

Angiogenesis Inhibitors↗
PubMed2002

Redox signaling of angiogenesis.

Reactive oxygen species (ROS) play a crucial role in vascular angiogenesis. Both in vitro and in vivo studies indicate that angiogenic response in vascular tissue is triggered by ROS signaling in a highly coordinated manner. It appears that massive amounts of ROS produced during ischemia and reperfusion in the vascular tissue, especially in heart, cause significant injury to the cardiomyocyte and endothelial cells. However, during the reperfusion, the same ROS potentiates a repair process and triggers a signal transduction cascade leading to angiogenesis. Although several other factors are likely to be involved for such angiogenic response, ROS certainly plays a crucial role as evident from its direct role as mediator of angiogenesis and inhibition of angiogenesis with free radical scavengers and/or antioxidants. Angiogenesis is regulated by redox-sensing transcription factors such as nuclear factor-kappaB, and oxidants such as hydrogen peroxide and free radicals, such as nitric oxide may function as second messengers in this highly coordinated process. Furthermore, expression of many angiogenic genes including those for vascular endothelial growth factor, fibroblast growth factor, platelet-derived growth factor, and receptors such as Flt-1, Flk-1, Ang-1, and Ang-2 are likely to be regulated by redox signaling. It is tempting to speculate that the angiogenic response is under the autocrine and/or paracrine control of one or more cytokines, which in turn is redox-regulated. Through angiogenesis, ROS appear to pave the way of repairing the vascular tissues that have been damaged during ischemia and reperfusion.

Animals↗
PubMedDate not supplied

Dual role of VEGF-induced heme-oxygenase-1 in angiogenesis.

Heme-oxygenase-1 (HO-1) is an inducible cytoprotective molecule that displays antioxidant, antiapoptotic, and antiinflammatory effects. In addition, HO-1 appears to have a complex role in angiogenesis. Recent in vivo studies report that vascular endothelial growth factor (VEGF) regulates HO-1 expression and activity in vascular endothelial cells (ECs) and that inhibition of HO-1 abrogates VEGF-induced endothelial activation and subsequent angiogenesis, while promoting VEGF-induced monocyte recruitment and inflammatory angiogenesis. HO-1 may also regulate the synthesis and activity of VEGF, resulting in a positive-feedback loop. In contrast, HO-1 activity has the opposite effect on lipopolysaccharide-driven inflammatory angiogenesis, inhibiting leukocyte invasion and preventing subsequent angiogenesis. In this review, we summarize the current understanding of the role of HO-1 in angiogenesis. We conclude that further investigation, using targeted molecular approaches specifically to alter HO-1 activity, are required to develop our understanding of the role of HO-1 and its products, carbon monoxide, biliverdin, bilirubin, and free iron in angiogenesis. We propose that during chronic inflammation, HO-1 has two roles, first an antiinflammatory action inhibiting leukocyte infiltration, and second, promotion of VEGF-driven noninflammatory angiogenesis, which facilitates tissue repair. Additional studies will help determine whether modulating the activity of HO-1 and/or its products has therapeutic potential in chronic inflammatory dise.

Animals↗
PubMed2006

Myoseverin is a potential angiogenesis inhibitor by inhibiting endothelial cell function and endothelial progenitor cell differentiation.

Myoseverin, a new microtubule-binding molecule, acts reversibly on myoblast proliferation without the cytotoxic effects displayed by nonpurine-based microtubule-disrupting molecules, like taxol, vinblastine, nocodazole, and the colchicines. In this study, we examined the effects of myoseverin on in vitro function of endothelial cells and endothelial progenitor cell differentiation in order to explore the possibility for the application of myoseverin as a reversible antiangiogenic agent. Myoseverin potently inhibited proliferation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner with an IC50 of approximately 8 microM. When myoseverin was removed after treatment for 3 days, all the cells pretreated at a concentration range of 2.5-80 microM resumed the cell growth. It also inhibited VEGF-induced HUVEC migration dose dependently. When mononuclear cells (MNCs) isolated from human cord blood were cultured on fibronectin-coated plates for 7 days, myoseverin decreased the number of adherent cells in a dose-dependent manner with IC50 of approximately 9 microM. It also suppressed the development of ac-LDL uptake ability as well as the expression of endothelial lineage markers, KDR, CD31, and vWF. Finally, it inhibited formation of HUVECs or ex vivo cultivated EPCs into capillary-like structure on Matri-gel and in vivo angiogenesis on the chick chorioallantoic membrane. Therefore, these results suggest that myoseverin can be effectively used for the inhibition of new vessel growth by inhibiting endothelial cell function and differentiation of progenitor cells.

Angiogenesis Inhibitors↗
PubMed2005

Microarray analysis of VEGF-C responsive genes in human lymphatic endothelial cells.

Vascular endothelial growth factor-C (VEGF-C) is considered one of the most important factors influencing lymphatic endothelial cell biology. The goal of this work was to characterize the gene expression response by lymphatic endothelial cells (LECs) to VEGF-C. Primary cultures of human microvascular LECs were exposed to 100 ng/mL VEGF-C for 30 minutes and 6 hours, and their lysates were evaluated by microarray analysis to determine changes in mRNA expression induced by VEGF-C. Characteristic of a response to a growth factor stimulus, the largest number of differentially expressed genes were transcription factors and cell cycle related. A number of genes known to be important in angiogenesis, tumorigenesis and tumor invasion, and the transport of proteins, solutes, and lipids were also affected. Interestingly, a number of genes related to lipid metabolism as well as neurogenesis and neurodegeneration were also responsive to VEGF-C stimulation. Further analysis of these genes may not only provide insight into the molecular mechanisms underlying lymphangiogenesis and associated pathogenesis, but may also identify other important roles of VEGF-C.

Cells, Cultured↗
PubMed1999

Coats' disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP gene: a role for norrin in retinal angiogenesis.

Coats' disease is characterized by abnormal retinal vascular development (so-called 'retinal telangiectasis') which results in massive intraretinal and subretinal lipid accumulation (exudative retinal detachment). The classical form of Coats' disease is almost invariably isolated, unilateral and seen in males. A female with a unilateral variant of Coats' disease gave birth to a son affected by Norrie disease. Both carried a missense mutation within the NDP gene on chromosome Xp11.2. Subsequently analysis of the retinas of nine enucleated eyes from males with Coats' disease demonstrated in one a somatic mutation in the NDP gene which was not present within non-retinal tissue. We suggest that Coats' telangiectasis is secondary to somatic mutation in the NDP gene which results in a deficiency of norrin (the protein product of the NDP gene) within the developing retina. This supports recent observations that the protein is critical for normal retinal vasculogenesis.

Amino Acid Substitution↗
PubMed2004

Soluble factors from human endometrium promote angiogenesis and regulate the endothelial cell transcriptome.

BACKGROUND: Angiogenesis and vascular remodeling play critical roles in the cyclical growth and regression of endometrium. They also appear to play roles in the pathogenesis of endometriosis. METHODS AND RESULTS: Supernatants were collected from cultured endometrium isolated from women with and without endometriosis. These supernatants induced endothelial cell proliferation and angiogenesis in vitro. They contained vascular endothelial growth factor (VEGF)-A, and their proliferative effects on endothelial cells were partially abrogated by a blocking anti-VEGF-A antibody. Gene array analysis showed that culture supernatants from proliferative phase endometrium, and to a lesser extent secretory phase endometrium, induced significant changes in the transcriptome of endothelial cells. We could not detect any association between endometriosis and the ability of endometrial-derived soluble factors to promote angiogenesis or to regulate the endothelial transcriptome. In addition, we could not detect any association between endometriosis and the concentration of VEGF-A in supernatants from cultured endometrium or in menstrual effluent. CONCLUSIONS: We have shown that endometrium cultured in vitro produced soluble factors, including VEGF-A, that promoted angiogenesis. Proliferative phase endometrium promoted significant endothelial cell transcriptome changes that appear overall to be pro-angiogenic. These transcriptome changes provide insight into the dynamic control of vessel structure on which both eutopic endometrium and endometriotic lesions depend.

Case-Control Studies↗
PubMed2006

Histological classification of chorionic villous vascularization in early pregnancy.

BACKGROUND: The objective of the study was to assess the reproducibility of a new classification for early pregnancy chorionic villous vascularization (Grade: I, normal; IIA, mild hypoplasia; IIB, severe hypoplasia and III, avascular) for routine microscopic examination in daily clinical practice. METHODS: In this observational study, four observers scored first trimester chorionic villous vascularization. Scoring was performed in microscopic slides of chorionic tissue obtained by D&C in 30 patients with early pregnancy loss due to empty sac (n = 10), fetal death (n = 10) and termination of pregnancy (n = 10) using the new classification. Ultrasonographic measurement of trophoblastic thickness (TT) at the implantation site was available in all patients and in a reference group of 100 ongoing singleton pregnancies. The vascularization score could therefore be related to the TT. RESULTS: The new classification resulted in a good-to-excellent agreement in histological scoring (0.73-0.90) between investigators (kappa 0.64-0.86). TT was not related to either vascularization or pregnancy outcome and only partly to hydropic degeneration. CONCLUSION: The vascularization scoring system is a simple, valid and effective method for assessment of chorionic villous vascularization. It is helpful in understanding the underlying cause of pregnancy loss, as the classification can distinguish between normal and abnormal embryonic development. We did not find either a relation between TT and pregnancy outcome or between TT and vascularization.

Adult↗
PubMedDate not supplied

Endometrial microvascular growth in normal and dysfunctional states.

As a tissue that exhibits rapid cyclical growth and shedding throughout the reproductive life of the female, human endometrium provides a good model for the study of normal physiological angiogenesis. The objective of this paper is to summarize recent data on endometrial vascular growth, present new data on regional variability in endothelial cell proliferation within the endometrium, and interpret this information in light of current knowledge of the mechanisms by which angiogenesis occurs. Conventional angiogenesis normally involves a series of steps which include endothelial cell activation, breakdown of the basement membrane, migration and proliferation of the endothelial cell, fusion of sprouts, and tube formation. Other mechanisms by which angiogenesis occurs include intussusception and vessel elongation. Using immunohistochemical techniques we have shown repeatedly that levels of endothelial cell proliferation within human endometrium do not show any consistent pattern across the different stages of the menstrual cycle, which is unexpected since significant vascular growth must occur during the proliferative phase, when the endometrium increases in thickness by up to 4-fold. There are two possible explanations for this; either there is no obligatory link between endometrial endothelial cell proliferation and new vessel formation, or there is significant variation in endothelial cell proliferation within different regions of the same uterus. Multiple samples from hysterectomy specimens subsequently demonstrated that the variability is due to real differences between individuals, as well as showing that the endothelial cell proliferation index is significantly elevated in functionalis compared with basalis. During these studies we observed that endothelial cell proliferation nearly always appeared inside existing endometrial vessels, rather than be associated with structures that could be identified as vascular sprouts. To explore further whether sprout formation occurs during endometrial angiogenesis, we investigated the immunohistochemical distribution of integrin alphavbeta3 on endometrial endothelial cells. As for endothelial cell proliferation, integrin alphavbeta3 immunostaining was seen only on endothelial cells that appeared within existing blood vessels. The results from these studies have major implications for our understanding of the mechanisms that control endometrial angiogenesis. The lack of correlation between menstrual cycle stage and endothelial cell proliferation index, or endothelial cell expression of integrin alphavbeta3, suggests that vascular growth is not under the overall control of oestrogen and progesterone.

Animals↗
PubMedDate not supplied

Clinical applications of colour Doppler energy imaging in the female reproductive tract and pregnancy.

This review describes the usefulness of colour Doppler energy (CDE) (or power Doppler) imaging to measure vascularization in the female reproductive tract. CDE imaging is characterized by an increased sensitivity to flow, and thus may be useful in low-flow states and when optimal Doppler angles cannot be obtained. In addition, longer segments of vessels and more individual vessels can be visualized with CDE imaging. The role of CDE imaging in the evaluation of stromal vasculature in normal and in polycystic ovaries is described, and the relationship between follicular vascularity and outcome following in-vitro fertilization are discussed, together with the findings obtained from the evaluation of thecal arteriole of corpus luteum in early pregnancy. The fundamental role of CDE imaging in differentiation among ovarian masses is also reviewed. We summarize the role of CDE imaging in pregnancy, and describe two new applications of three-dimensional power Doppler sonography and the use of ultrasound contrast media. In conclusion, CDE imaging can replace conventional colour Doppler when the information on the direction of flow is not useful. Moreover, the technique appears superior to others for describing microvascular architecture and determining the presence or absence of flow.

Corpus Luteum↗
PubMed2004

Abundant retention and release of connective tissue growth factor (CTGF/CCN2) by platelets.

Wound healing and tissue regeneration are usually initiated by coagulation followed by fibrous tissue formation. In the present study, we discovered an abundance of connective tissue growth factor (CTGF/CCN2) in human platelets, which was released along with the coagulation process. The CTGF/CCN2 content in platelets was 10-fold higher than that in arterial tissue. Furthermore, the CTGF/CCN2 content in a single platelet was computed to be more than 20-fold higher than that of any other growth factor reported. Considering that CTGF/CCN2 promotes angiogenesis, cartilage regeneration, fibrosis and platelet adhesion, it may be now regarded as one of the major functional components of platelets.

Blood Platelets↗