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Protocols designed for the adipogenic differentiation of human and mouse cells are commonly used for inducing the adipogenesis of bovine stromal vascular cells. However, likely due to metabolic differences between ruminant and non-ruminant animals, these methods result in only few cells undergoing complete adipogenesis with minimal lipid droplet accumulation. Here, we discuss the development of an adipogenic differentiation protocol for bovine primary cells through a three-dimensional spheroid culture. Stromal vascular cells derived from bovine intramuscular fat were isolated and stored in liquid nitrogen before culturing. Cells were cultured in hanging drops for 3 days to allow for the formation of spherical structures. The spheroids were then transferred to cell culture plates with endothelial basal medium-2 for 3 days and in Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with a standard adipogenic cocktail for 3 additional days, which were then allowed to fully differentiate for 3 days in DMEM supplemented with insulin. Compared with conventional two-dimensional culture, cells in a three-dimensional spheroid culture system had higher adipogenic gene expression and consequently contained more adipocytes with larger lipid droplets. In addition, endothelial induction of spheroids prior to adipogenic differentiation is essential for efficient induction of adipogenesis of bovine stromal vascular cells, mimicking in vivo adipose development. In summary, the newly developed three-dimensional spheroid culture method is an efficient way to induce adipogenic differentiation and study adipose development of cells derived from ruminant animals, which also can be used for studying the role of angiogenesis in adipose development.
Lead is one of the environmental pollutants with cardiovascular toxicity. The embryos are particularly sensitive to lead exposure, because it can move through the blood-placental barrier and the blood-brain barrier easily during embryonic development. Cerebral cavernous malformations 3 (CCM3) gene plays an important role in cardiovascular development, mainly affecting cell proliferation, differentiation and apoptosis. In this study, we established a blood vessel development model of mouse embryos in order to imitate human people with CCM3 genes defects and exposing to environment toxin Pb in utero. We would like to determine the interaction of Pb and CCM3 gene on vascular development, and to explore the mechanisms. We found that the yolk sac of CCM3 heterozygous mice embryo showed abnormal morphology at E11.5 after lead treatment comparing with wild type (WT) mice without lead exposure, meanwhile it showed more angiogenesis and vascular remodeling in the hematoxylin and eosin stained sections of the CCM3+/− yolk sac with lead exposure. We also found that the similar effect of Pb and CCM3 gene on mitochondrial DNA (mtDNA) copy number in vivo and in vitro. Mitochondrial morphology and function also changed in primary human umbilical vein endothelial cells after lead exposure. Besides, it was found that the HIF-1α and TFAM which have close relationship with mtDNA biogenesis showed similarly increasing messenger RNA expression in both human and mouse-derived primary cells with lead treated and CCM3 gene knockout. All of the above results indicated that lead and CCM3 might damage endothelial cells through mitochondria pathway and eventually both affected angiogenesis.
Angiogenesis is a closely controlled biological process that takes place during fetal development of blood vessels and wound healing, and includes the development of new blood vessels from preexisting blood vessels. Tumor angiogenesis is a means by which tumors obtain oxygen, nutrition and promote tumor growth. Angiogenesis-regulating proteins are therefore ideal biomarkers in the study of tumor pathophysiology. In our laboratory, a new in silico-designed analogue of 2-methoxyestradiol has been synthesized with angiogenic properties, namely 2-ethyl-3-O-sulfamoyl-estra-1,3,5(10)16-tetraene (ESE-16). The ex vivo influence of ESE-16 on angiogenesis and morphology in platelets of healthy participants was investigated. Scanning electron microscopy revealed no morphological changes in ESE-16-treated platelets. The possible antiangiogenic effect of ESE-16-exposed platelets was determined by means of flow cytometry measurement of angiogenic protein levels, which were significantly increased after platelets were added to tumorigenic breast epithelial cells. This indicates that binding of platelets to cancer cells causes differential release of platelet constituents. Vascular endothelial growth factor levels were decreased in platelets, whereas platelet-derived growth factor and matrix metallopeptidase-9 levels were not significantly affected in platelets. In light of the above-mentioned data, further investigation of ESE-16’s influence on morphology and angiogenic markers in platelets of cancer patients is warranted.
This study aimed to evaluate the association of a disintegrin and metalloproteinase-33 protein (‘ADAM-33’) expression in vocal polyp formation and to determine its correlation with clinical characteristics.
Medical charts and histological sections of 32 patients diagnosed with vocal polyps who underwent surgery were analysed. Controls were histopathologically normal vocal fold tissues obtained from 36 patients who underwent surgery for laryngeal squamous cell carcinoma. Immunohistochemical staining was performed to detect ADAM-33 expression in epithelial cells, stroma and vessels.
All epithelial, stromal and vascular staining scores were significantly greater in polyp tissue than in controls (p < 0.001). Stromal ADAM-33 staining scores were higher in vocal polyp patients with a symptom duration of less than six months (p < 0.05). Vocal overuse or the presence of reflux symptoms, sinonasal symptoms or allergy did not affect ADAM-33 immunostaining scores (p = 0.05).
In this study, ADAM-33 immunostaining was significantly increased in vocal polyps. Therefore, over-expression of this protein may be associated with vocal polyp pathogenesis.
Glioblastoma is the most common and malignant primary brain tumour in adults. Maximum feasible surgical resection, radiotherapy and temozolomide chemotherapy at initial diagnosis have improved prognosis but rapid recurrence is typical and survival remains brief. There is an urgent need for effective new treatments and approval of the antiangiogenic agent bevacizumab for recurrent glioblastoma by Health Canada in 2009 has been the most notable recent therapeutic advance for this disease. This review with illustrative case studies highlights how bevacizumab has been incorporated into the treatment of glioblastoma in Canada and describes the ongoing controversies surrounding its clinical application.
Cancer treatment using the antiangiogenic agents targets the evolution of the tumor vasculature. The aim is to significantly reduce supplies of oxygen and nutrients, and thus starve the tumor and induce its regression. In the paper we consider well established family of tumor angiogenesis models together with their recently proposed modification, that increases accuracy in the case of treatment using VEGF antibodies. We consider the optimal control problem of minimizing the tumor volume when the maximal admissible drug dose (the total amount of used drug) and the final level of vascularization are also taken into account. We investigate the solution of that problem for a fixed therapy duration. We show that the optimal strategy consists of the drug-free, full-dose and singular (with intermediate values of the control variable) intervals. Moreover, no bang-bang switch of the control is possible, that is the change from the no-dose to full-dose protocol (or in opposite direction) occurs on the interval with the singular control. For two particular models, proposed by Hahnfeldt et al. and Ergun et al., we provide additional theorems about the optimal control structure. We investigate the optimal controls numerically using the customized software written in MATLAB®, which we make freely available for download. Utilized numerical scheme is based on the composition of the well known gradient and shooting methods.
Tumour vasculature plays an important role in the development, maintenance and sustainability of a tumour. Endothelial cells which are recruited into the tumour stroma facilitate the formation of essential blood vessels that deliver nutrients and oxygen to tumour cells. A growing body of research is showing that there are synergistic anti-tumour effects when anti-vascular agents are combined with radiation. More recent reports have described favourable radiation response as a function of vascular targeting and blood vessel breakdown, primarily through interactions of radiation with vascular endothelial cells. Vascular disrupting agents are being utilised in several forms that include molecular targeting, biophysical assault and biological interference.
In the present review, we examine current advances in anti-vascular agents to enhance tumour response when combined with radiation therapy.
A comprehensive literature search was conducted on the US National Library of Medicine, National Institutes of Health (PubMed) using the following search keywords: vascular disrupting agents, radiation sensitisation, anti-angiogenic therapy, anti-vascular therapy, radiation therapy.
Current research suggests the applicability of vascular disrupting agents as an effective radiation sensitisation agent. Pre-clinical and clinical trials have been well developed to form the theoretical framework to apply this powerful modality to the treatment of cancer.
Severe cyanosis due to pulmonary arteriovenous fistulas occurs often after a bidirectional superior cavopulmonary anastomosis (Glenn operation) and also in some congenital anomalies in which hepatic venous blood bypasses the lungs in the first passage. Relocation of hepatic flow into the lungs usually causes these fistulas to disappear. Similar pulmonary arteriovenous fistulas are observed in hereditary haemorrhagic telangiectasia, and in liver disease (hepatopulmonary syndrome). There is no convincing identification yet of a responsible hepatic factor that produces these lesions. Candidates for such a factor are reviewed, and the possibility of angiotensin or bradykinin contributing to the fistulas is discussed.
Angiogenesis is important for tumour vascularisation and growth, and is therefore a promising target for cancer therapy. The present study reports inhibition of in vitro angiogenesis in human umbilical vein endothelial cells (HUVEC) as well as in rat aortic rings at physiological concentrations of lycopene, that is, 1–2 μmol/l. At a final concentration of 1·15 μmol/l, a significant reduction (P < 0·05) in network branching, that is, junction numbers, the number of tubules and tubule length, was observed in both HUVEC as well as in the rat aortic rings. The inhibitory effect of lycopene was independent of the presence of the pro-angiogenic agents, vascular endothelial growth factor and TNF-α. The anti-angiogenic effects of lycopene in the present study were shown at a concentration that should be achievable by dietary means. These results extend our knowledge of one of the putative anti-cancer actions of lycopene.
Ovarian folliculogenesis in mammals is a complex process. Several compounds have been tested during in vitro culture of follicular cells for a better understanding of the mechanisms and factors related to ovarian folliculogenesis in mammals. From these compounds, vascular endothelial growth factor (VEGF) can be highlighted, as it is strongly associated with angiogenesis and, in recent years, its presence in ovarian cells has been investigated extensively. Previous studies have shown that the presence of VEGF protein, as well as mRNA expression of its receptor 2 (VEGFR-2) increases during follicular development. Therefore, it is likely that the interaction between VEGF and VEGFR-2 is crucial to promote follicular development. However, few studies on the influence of this factor on follicular development have been reported. This review addresses aspects related to the structural characterization and mechanism of action of VEGF and its receptors, and their biological importance in the ovary of mammals.
We introduce a phenomenological model for anti-angiogenic therapy in the treatment of metastatic cancers. It is a structured transport equation with a nonlocal boundary condition describing the evolution of the density of metastases that we analyze first at the continuous level. We present the numerical analysis of a lagrangian scheme based on the characteristics whose convergence establishes existence of solutions. Then we prove an error estimate and use the model to perform interesting simulations in view of clinical applications.
The great majority of women with advanced ovarian cancer will relapse and die from the disease. Angiogenesis is particularly relevant to ovarian cancer. Tumour vascular endothelial growth factor (VEGF) overexpression is associated with tumour angiogenesis, malignant progression and metastasis, ascites formation and early recurrence and death from the disease. Chemotherapy and vascular disrupting agents (VDAs) can cause mobilisation of bone marrow progenitor cells, including circulating endothelial progenitor cells (CEPs), which could theoretically increase angiogenesis. Two trials of combination therapy that included bevacizumab have suggested discrepancies between CA125 and RECIST response evaluation. VDAs selectively target pre-existing tumour vasculature, leading to rapid tumour cell ischaemia and death. The decrease in vascular tumour perfusion seen using dynamic contrast imaging suggests dynamic methods such as DCE-MRI, positron emission tomography-computed tomography (PET/CT) and MR spectroscopy in phase I and II trials may give an early indication of antivascular effect.
Medical treatment of endometriosis is a necessary step in the management of the disease due to its high rate of recurrence and different clinical situations. Women with endometriosis present a peritoneal environment with increased angiogenic activity. Angiogenesis involves the formation of new blood vessels released by pre-existing vessels. Several antiangiogenic agents have been successfully tested in experimental models of endometriosis inhibiting new vessel formation. These compounds target specifically the endothelial cells without penetration in the tissues. Several anticancer drugs with antiangiogenic potential have been found to have a detrimental effect on reproductive function in both animal models and patients. The studies in experimental oncological models demonstrated that dopamine agonists (DA) have an antiangiogenic effect promoting the vascular endothelial growth factor receptors (VEGFR)-2 endocytosis in endothelial cells, preventing the VEGF-VEGFR-2 union and avoiding receptor phosphorylation and signal cascade.
Advances in the diagnosis and treatment of childhood, adolescent and adult cancer have increased the life expectancy of premenopausal women with the disease. Oncological indications for ovarian tissue cryopreservation are summarized. Patients undergoing oophorectomy for prophylaxis may potentially benefit from ovarian cryopreservation. There have been numerous reported cases of autotransplantation of cryopreserved ovarian tissue, either to an orthotopic or heterotopic site. Approximately one third of young women exposed to chemotherapy develop ovarian failure. It is our ethical responsibility to propose cryopreservation of ovarian tissue to all adolescents and young women under institutional review board (IRB) protocols having to undergo chemotherapy with alkylating agents. Research programs need to determine whether active angiogenesis can be induced to accelerate the process of neovascularization in grafted tissue, if isolated human follicles can be grafted or, indeed, if microvascular re-anatomosis of an entire cryopreserved ovary is a valuable option.
Successful metazoan parasitism, among many other factors, requires a supply of nutrients and the removal of waste products. There is a prerequisite for a parasite-defined vasculature. The angiogenic mechanism(s) involved presumably depend on the characteristics of the tissue- and vascular system-dwelling, parasitic helminths. Simplistically, 2 possibilities or a combination of both have been considered in this review. The multifactorial induction of parasitic helminth-associated neovascularization could arise through, either a host-, a parasite- or a host-/parasite-dependent, angiogenic switch. Most studies appear to support the first and third hypotheses, but evidence exists for the intrahepatic cestode Echinococcus multilocularis, the free-living nematode Caenorhabditis elegans and the intravascular trematode Schistosoma mansoni for the second inference. In contrast, the nematode anti-coagulant protein NAPc2 from adult Ancylostoma caninum is also an anti-angiogenic factor.
Aging is the single most significant risk factor for erectile dysfunction (ED), leading to structural modification of cavernous tissue and altering expression of vascular growth factors. The angiopoietin/Tie2 system has been recently considered as a potential target for therapy of vascular disorders, including ED. Hence, the aim of this study was to analyze expression of angiopoietin1 (Ang1), angiopoietin2 (Ang2), and their receptor Tie2 in corpus cavernosum (CC) of rat during aging (6, 12, 18, and 24 months). The expression of Ang1, Ang2, and Tie2 was studied by immunohistochemistry and immunofluorescence, followed by semiquantification after Western blotting. Both Ang1 and Ang2 were localized mainly in perivascular smooth muscle and endothelial cells, while Tie2 was strictly detected at the vascular endothelium. A significant decrease in Ang2's expression was observed at 12 months when compared with 6-month-old rats, a tendency that reverses in older animals. No significant differences were demonstrated for Ang1 or Tie2, which is consistent with their constitutive expression in CC. The ratios Ang1/Tie2 and Ang2/Tie2 were also calculated and both decrease during aging, while no marked variation was observed for Ang1/Ang2. Our results suggest that the angiopoietin/Tie2 system participate in the vascular maintenance and remodeling of the CC during aging.
This chapter discusses placental angiogenesis, including information on placental neovascular formation as well as transformation of the vessels during gestation. By 4 weeks' gestation, the cytotrophoblasts proliferate and form the primary villi. The placenta structurally provides a very intimate relationship between the maternal blood and fetal blood. Once blood vessels are formed within the tertiary villi, they begin to remodel and adapt to the changing needs of the growing embryo and fetus. Placental angiogenesis is very complex and depends on an appropriate balance between pro-angiogenic and anti-angiogenic factors. Dysregulation of placental angiogenesis often leads to pregnancy-related diseases. Three common adverse pregnancy outcomes have been associated with defective placental vascularization: spontaneous abortion, intrauterine growth restriction (IUGR), sometimes referred to as small-for-gestational age (SGA), and preeclampsia (PE). Further characterization of angiogenesis in placental development will better inform clinicians and scientists about healthy and pathological pregnancies.
Patients with cyanotic congenital cardiac disease often develop major aortopulmonary collaterals. Vascular endothelial growth factor is a key promoter of angiogenesis. Its soluble receptor-1 acts as a potent antagonist. We studied 30 infants with cyanotic congenital cardiac disease and 27 infants with acyanotic congenital cardiac disease. Central venous plasma vascular endothelial growth factor and soluble vascular endothelial growth factor receptor-1 levels were measured before, and 24 and 96 hours after surgery. There was no difference between plasma vascular endothelial growth factor levels in infants with cyanotic and those with acyanotic congenital cardiac disease. In cyanotic infants, the soluble vascular endothelial growth factor receptor-1 levels tended to be higher than in the acyanotic infants. In conclusion, there is no significant difference in the plasma levels of vascular endothelial growth factor and its soluble receptor-1 between infants with cyanotic and those with acyanotic congenital cardiac disease.
Power Doppler ultrasound (US), in combination with three-dimensional US and virtual organ computer-aided analysis (VOCAL), is a very good approach for investigating the global ovarian vascular network and its correlation with ovarian response in assisted reproductive technology (ART). An ovarian vascular map is easily obtained from a sagittal section of the ovary. Three-dimensional US has become a key tool for diagnosing uterine malformations. Leiomyomas and endometrial polyps are the most frequent benign uterine pathologies, and both can interfere with the reproductive process. The human endometrium undergoes intense angiogenesis during menstrual cycle, and angiogenesis is a key process for successful embryo implantation and development. In reproductive medicine, it is crucial to exclude ectopic pregnancy as early as possible. 3D US is a more accurate technique for evaluating the relationship between the gestational sac and uterine septum and for differentiating between a cornual pregnancy and a displaced intracavitary pregnancy.
Over the past decade or so, there have been a large number of modelling approaches aimed
at elucidating the most important mechanisms affecting the formation of new capillaries
from parent blood vessels — a process known as angiogenesis. Most studies have focussed
upon the way in which capillary sprouts are initiated and migrate in response to
diffusible chemical stimuli supplied by hypoxic stromal cells and leukocytes in the
contexts of solid tumour growth and wound healing. However, relatively few studies have
examined the important role played by blood perfusion during angiogenesis and fewer still
have explored the ways in which a dynamically evolving vascular bed architecture can
affect the distribution of flow within it. From the perspective of solid tumour growth
and, perhaps more importantly, its treatment (e.g. chemotherapy), it would clearly be of
some benefit to understand this coupling between vascular structure and perfusion more
fully. This paper focuses on the implications of such a coupling upon chemotherapeutic,
anti-angiogenic, and anti-vascular treatments.
In an extension to previous work by the authors, the issue of pericyte recruitment during
vessel maturation is considered in order to study the effects of different anti-vascular
and anti-angiogenic therapies from a more rigorous modelling standpoint. Pericytes are a
prime target for new vascular disrupting agents (VDAs) currently in clinical trials.
However, different compounds attack different components of the vascular network and the
implications of targeting only certain elements of the capillary bed are not immediately
clear. In light of these uncertainties, the effects of anti-angiogenic and anti-vascular
drugs are re-examined by using an extended model that includes an interdependency between
vessel remodelling potential and local pericyte density. Two- and three-dimensional
simulation results are presented and suggest that it may be possible to identify a
VDA-specific “plasticity window” (a time period corresponding to low pericyte density),
within which a given VDA would be most effective.