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Slice simulation from a model of the parenchymous vascularization to evaluate texture features: work in progress.

RATIONALE AND OBJECTIVES: To demonstrate the usefulness of a model of the parenchymous vascularization to evaluate texture analysis methods. METHODS: Slices with thickness varying from 1 to 4 mm were reformatted from a 3D vascular model corresponding to either normal tissue perfusion or local hypervascularization. Parameters of statistical methods were measured on 16128x128 regions of interest, and mean values and standard deviation were calculated. For each parameter, the performances (discrimination power and stability) were evaluated. RESULTS: Among 11 calculated statistical parameters, three (homogeneity, entropy, mean of gradients) were found to have a good discriminating power to differentiate normal perfusion from hypervascularization, but only the gradient mean was found to have a good stability with respect to the thickness. Five parameters (run percentage, run length distribution, long run emphasis, contrast, and gray level distribution) were found to have intermediate results. In the remaining three, curtosis and correlation was found to have little discrimination power, skewness none. CONCLUSION: This 3D vascular model, which allows the generation of various examples of vascular textures, is a powerful tool to assess the performance of texture analysis methods. This improves our knowledge of the methods and should contribute to their a priori choice when designing clinical studies.

Blood Vessels↗

Role of angiopoietins in reproductive tract angiogenesis.

UNLABELLED: Components of the female reproductive system undergo a number of programmed angiogenic processes coupled with cyclic evolution and decline of ovarian, endometrial, and placental structures. The development of a new vascular network requires a remarkable degree of coordination between different cell types undergoing complex changes. This implies that the expression of the inciting angiogenic factors are hormone dependent. Recently, a second family of vascular endothelial growth factors was identified, the angiopoietins. Angiopoietins are vascular endothelial cell-specific growth factors that play important roles principally during the later stages of angiogenesis, after the induction of new capillaries by vascular endothelial growth factor (VEGF). There are four known angiopoietins, and their specificity for the vascular endothelium results from the restricted expression pattern of their tyrosine kinase receptor, Tie2. In this review, we discuss the molecular characterization and mechanism of action of angiopoietin-1 and angiopoietin-2 in reproductive tract angiogenesis. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader will be able to describe the angiogenic process and specifically explain the role of angiopoietics in reproductive tract angiogenesis and compare the differences between the various proteins that are involved in angiogenesis.

Angiopoietin-1↗

Vascular endothelial growth factor, a specific regulator of angiogenesis.

Vascular endothelial growth factor is a diffusible endothelial cell-specific mitogen and angiogenic factor that can also increase vascular permeability. The vascular endothelial growth factor receptors are specifically expressed on the cell surface of vascular endothelial cells. Recent studies point to vascular endothelial growth factor as a major regulator of physiological angiogenesis, such as developmental and reproductive angiogenesis. In addition vascular endothelial growth factor appears to be a crucial mediator of blood vessel growth associated with tumors and proliferative retinopathies. Antivascular endothelial growth factor antibodies have the ability to suppress the growth of a variety of tumor cell lines in nude mice and can also inhibit angiogenesis in animal models of intra-ocular neovascularization. Furthermore vascular endothelial growth factor administration promotes collateral vessel growth and results in functional improvement in animal models of coronary or limb ischemia.

Animals↗

Fibrosis and angiogenesis.

Research during the past few years has contributed vastly to a better understanding of fibrosis and angiogenesis. Although studies to understand the molecular processes associated with fibrosis and angiogenesis were performed independently of each other, some common parallels have emerged. Translation of these observations into potential therapeutic possibilities needs further exploration.

Animals↗

Targeting angiogenic processes by combination low-dose paclitaxel and radiation therapy.

Tumor growth and angiogenesis are interdependent. Paclitaxel and radiation therapy are commonly used in the clinic, in a number of disease sites, requiring high dosages of both drug and radiation for cure. Paclitaxel (Taxol) is a diterpenoid with antitumor activity against a variety of human neoplasms and can amplify the cytotoxic effect of ionizing radiation in vitro, presumably by inducing arrest at metaphase, known to be a very radiosensitive phase of the cell cycle. Little is known about how angiogenesis is affected by paclitaxel when the combination of paclitaxel and radiation are used. We have evaluated the combination of paclitaxel and radiation at various concentrations, on cytokine-induced angiogenesis in vitro with the goal of determining whether reduction of radiation and paclitaxel doses is possible without sacrificing efficacy. We have found that paclitaxel inhibited endothelial cell proliferation, migration, and tube formation (differentiation) at one-tenth the concentration needed to achieve a similar effect on tumor cell lines. In combination with radiation, inhibition of endothelial cell function was additive and increased twofold. The combination of low-dose paclitaxel and radiation suggests a complementary strategy with potential clinical ramifications to target angiogenesis-dependent malignancies.

Animals↗

Angiogenesis and lymphangiogenesis: highlights of the past year.

PURPOSE OF REVIEW: The purpose of this review is not to provide an extensive overview of well-established mechanisms of angiogenesis and lymphangiogenesis but rather to highlight several recent key studies that constituted a significant conceptual or medical advancement to the field during the past year or so. The authors apologize for their inability, because of space restrictions, to reference all other relevant work of the past or previous years. RECENT FINDINGS: In 1993, fewer than 400 studies on angiogenesis were published. During the past year alone, more than 4000 angiogenesis studies were reported, making angiogenesis one of the most rapidly growing fields. Moreover, the first studies on lymphangiogenesis were published only a couple of years ago. A milestone in the field in the past year has been the first successful report that the angiogenesis inhibitor bevacizumab (Avastin), an antibody against vascular endothelial growth factor, prolonged the survival of colorectal and renal cancer patients in phase 3 clinical trials. This remarkable achievement provides great promise and hope for the future development of therapeutic strategies to inhibit or stimulate angiogenesis. SUMMARY: The intensive search for antiangiogenic and proangiogenic mechanisms during the past decade is starting to translate into clinical promise. Further discovery of novel pathways and concepts in angiogenesis may lead to the optimization and refinement of current strategies to improve the clinical benefit and therapeutic safety for a vast number of patients with angiogenesis-related disease.

Angiogenesis Inhibitors↗

Contribution of endothelial progenitors and proangiogenic hematopoietic cells to vascularization of tumor and ischemic tissue.

PURPOSE OF REVIEW: During the last several years, a substantial amount of evidence from animal as well as human studies has advanced our knowledge of how bone marrow derived cells contribute to neoangiogenesis. In the light of recent findings, we may have to redefine our thinking of endothelial cells as well as of perivascular mural cells. RECENT FINDINGS: Inflammatory hematopoietic cells, such as macrophages, have been shown to promote neoangiogenesis during tumor growth and wound healing. Dendritic cells, B lymphocytes, monocytes, and other immune cells have also been found to be recruited to neoangiogenic niches and to support neovessel formation. These findings have led to the concept that subsets of hematopoietic cells comprise proangiogenic cells that drive adult revascularization processes. While evidence of the importance of endothelial progenitor cells in adult vasculogenesis increased further, the role of these comobilized hematopoietic cells has been intensely studied in the last few years. SUMMARY: Angiogenic factors promote mobilization of vascular endothelial growth factor receptor 1-positive hematopoietic cells through matrix metalloproteinase-9 mediated release of soluble kit-ligand and recruit these proangiogenic cells to areas of hypoxia, where perivascular mural cells present stromal-derived factor 1 (CXCL-12) as an important retention signal. The same factors are possibly involved in mobilization of vascular endothelial growth factor receptor 2-positive endothelial precursors that may participate in neovessel formation. The complete characterization of mechanisms, mediators and signaling pathways involved in these processes will provide novel targets for both anti and proangiogenic therapeutic strategies.

Animals↗

Massive inborn angiogenesis in the brain scarcely raises cerebral blood flow.

The functional consequences of increased capillary densities in the brain resulting from vascular endothelial growth factor (VEGF165) overexpression are unknown. Therefore, the authors measured local CBF using the iodo-[14C]antipyrine technique in transgenic mice expressing brain-specifically sixfold higher VEGF165 levels and in nontransgenic littermates. To reveal possible compensatory vasoconstriction, CBF was also measured during severe hypercapnia (Paco2 > 130 mm Hg). Simultaneously, local capillary density, perfusion state, and blood-brain-barrier permeability were assessed. Using the 2-[14C]deoxyglucose method, metabolic effects of VEGF over-expression could be excluded. In transgenic mice all capillaries showed normal morphology and a tight blood-brain barrier. However, 3% nonperfused capillaries in some brain structures indicate ongoing angiogenesis. Capillary density was drastically increased in transgenic mice in white matter structures (70% to 185%), the dentate gyrus (143%), and caudate nucleus (86%). In all other brain structures investigated, capillary densities were moderately increased by approximately 20%. Normocapnic CBF did not differ between transgenic and nontransgenic mice. During maximal hypercapnic vasodilation, CBF was 20% to 30% higher in transgenic mice, although only in brain structures where capillary density was increased more than twofold. These findings suggest that attenuated CBF in transgenic mice during normocapnia is only partly due to a compensatory vasoconstriction, and that microvascular networks in transgenic brains might be ineffectively constructed.

Animals↗

The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis.

PTEN is an important tumor suppressor gene. Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePten(flox/+) mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85alpha and p110gamma. In vitro, Tie2CrePten(flox/+) endothelial cells showed enhanced proliferation/migration. Tie2CrePten(flox/flox) mice died before embryonic day 11.5 (E11.5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes depend strongly on p110gamma rather than on p85alpha and were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2. Pten is thus indispensable for normal cardiovascular morphogenesis and post-natal angiogenesis, including tumor angiogenesis.

Animals↗

Structural basis for the functions of endogenous angiogenesis inhibitors.

Tipping the angiogenic balance between pro- and antiangiogenic stimuli to favor vasculature induction and enhanced angiogenesis is a key event in the growth and progression of tumors. Recently, we demonstrated that the genetic loss of normal physiological levels of individual endogenous inhibitors of angiogenesis leads to a change in the balance between proangiogenic stimulators and their inhibitors, thus favoring enhanced angiogensis and increased tumor growth. Therefore, these endogenous angiogenesis inhibitors provide a physiological threshold against the induction of angiogenesis. The antiangiogenic activities of endostatin, tumstatin, and thrombospondin-1 are evaluated and correlated with their three-dimensional structure and active sites, deriving a structural basis for their activities. Collectively, structural analysis of all three inhibitors demonstrates that the active antiangiogenic sites on these molecules are exposed on the surface and available to bind their putative integrin receptors on proliferating endothelial cells.

Amino Acid Sequence↗

Physiologically based modeling of 3-D vascular networks and CT scan angiography.

In this paper, a model-based approach to medical image analysis is presented. It is aimed at understanding the influence of the physiological (related to tissue) and physical (related to image modality) processes underlying the image content. This methodology is exemplified by modeling first, the liver and its vascular network, and second, the standard computed tomography (CT) scan acquisition. After a brief survey on vascular modeling literature, a new method, aimed at the generation of growing three-dimensional vascular structures perfusing the tissue, is described. A solution is proposed in order to avoid intersections among vessels belonging to arterial and/or venous trees, which are physiologically connected. Then it is shown how the propagation of contrast material leads to simulate time-dependent sequences of enhanced liver CT slices.

Algorithms↗

Angiogenesis.

The formation of new blood vessels, angiogenesis, is a complex process which is central to normal development and homeostasis. However, uncontrolled angiogenesis plays a critical role in both inflammatory and neoplastic disorders. Our understanding of angiogenesis has expanded greatly over the past two decades due to the development of in vivo and in vitro models to study this important process. A variety of cytokines and growth factors have been shown to induce new blood vessel formation in vivo, and in vitro studies have been able to define whether agents have direct or indirect effects upon vascular endothelial cells. Our improved understanding of the mechanisms which regulate angiogenesis has now created important opportunities for the development of new therapies for the treatment of inflammatory and neoplastic skin disease.

Endothelial Growth Factors↗

Inhibition of angiogenesis by rhizoxin, a microbial metabolite containing two epoxide groups.

Previous studies by our and other groups have shown that microbial products containing more than one epoxide group, including eponemycin, radicicol, depudecin and AGM-1470, exhibits anti-angio-genic activity in an in vivo assay system involving chorioallantoic membranes (CAMs) of growing chick embryos. Based on these findings, rhizoxin, a microbial metabolite that contains two epoxide groups and exhibits anti-tubulin activity, was tested for anti-angiogenic activity in a CAM assay system. Rhizoxin caused dose-dependent inhibition of embryonic angiogenesis, the ID50 value being 2 ng (3.2 pmol) per egg. In addition, this compound (2 mg/kg i.p.) significantly suppressed neovascularization induced by M5076 mouse tumor cells in a mouse dorsal air sac assay system, compared to the vehicle alone (P < 0.05). These results indicate that rhizoxin is a novel inhibitor of angiogenesis, and that is has potential as a new therapeutic agent for cancer.

Animals↗