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PubMed2001

The novel tubulin-binding drug BTO-956 inhibits R3230AC mammary carcinoma growth and angiogenesis in Fischer 344 rats.

BTO-956 [methyl-3,5-diiodo-4-(4'-methoxyphenoxy)benzoate], a novel tubulin-binding drug and thyroid hormone analogue, was originally found to inhibit human carcinoma cell proliferation in vitro and to have potent growth delay activity in human breast and ovarian carcinoma xenografts in nude mice. Here we report that BTO-956 given to Fischer 344 rats also inhibits corneal angiogenesis and the growth and neovascularization of the R3230Ac rat mammary carcinoma tumor implanted in skin-fold window chambers. Hydron pellets containing recombinant human basic fibroblast growth factor (50 ng) and Sucralfate (20 microg) were implanted into surgically created corneal micropockets (day 0). BTO-956 was administrated by oral gavage (500 mg/kg, twice a day for 6 days) on days 1-6 (controls received vehicle alone). On day 7, rats received retrograde infusions of India ink via the thoracic aorta to visualize the corneal vasculature. Digitized images of slide-mounted corneas from control and treated animals were taken with a microscope. For the tumor growth and angiogenesis study, small pieces of R3230Ac tumor from a donor rat were implanted into surgically prepared window chambers (day 0). BTO-956 was given during days 5-11, and images of the tumors and their vasculature were recorded on day 12. No body weight loss was observed in either study. BTO-956 significantly inhibited corneal angiogenesis (by 50-80%), as assessed by measurements of limbal circumference displaying neovascularization, vessel length, vascularized area, and vascular area density. In the window chamber assay, tumors from treated animals were >50% smaller than tumors in control animals. In addition, vascular length densities in peripheral tumor zones were 30% less in treated compared with control animals. Together, these findings demonstrate that BTO-956 can inhibit angiogenesis induced by a growth factor in the rat cornea and in the peripheral area of implanted tumors, where tumor angiogenesis is most active.

Animals↗
PubMed2002

Hemodynamics in vasculogenic mimicry and angiogenesis of inflammatory breast cancer xenograft.

In the present study, we examined hemodynamics in vasculogenic mimicry (VM) and angiogenesis of inflammatory breast cancer (IBC) xenografts (WIBC-9), having previously reported on the unique histological features and molecular basis of these processes (K. Shirakawa et al., Cancer Res., 61: 445-451, 2001). Histologically, the WIBC-9 xenografts exhibited invasive ductal carcinoma with a hypervascular structure (angiogenesis) in the tumor margin and VM without endothelial cells, central necrosis, or fibrosis in the tumor center. Results of molecular analysis indicated that WIBC-9 had a vasculogenic phenotype, including expression of Flt-1 and Tie-2. Comparison of WIBC-9 with an established non-IBC xenograft (MC-5), using time-coursed dynamic micromagnetic resonance angiography analysis (with our newly developed intravascular macromolecular magnetic resonance imaging contrast agent), electromicroscopy, and immunohistochemistry, demonstrated blood flow and a VM-angiogenesis junction in the central area of the WIBC-9 tumor. It has previously been considered impossible to prove a connection between VM and angiogenesis using angiography, because there are no intravascular macromolecular magnetic resonance imaging contrast agents that do not exhibit significant leakage through the vascular wall. In the present study, laser-captured microdissection was performed in regions of WIBC-9 tumors that exhibited VM without endothelial cells, central necrosis, or fibrosis, revealing expression of human-Flt-1 and human-Tie2 and the absence of human-CD31, human-endothelin B receptor, and human-thrombin receptor. These facts led us to hypothesize that the VM of WIBC-9 involves hemodynamics that serve to feed WIBC-9 cells, and this in turn suggests a connection between VM and angiogenesis.

Animals↗
PubMed2001

Tumor angiogenesis as a prognostic factor in oral cavity carcinomas.

Currently, lymph node metastasis and thickness of the tumor are the gold standard as a predictor of survival in patients with oral cavity squamous cell carcinoma (OSCC). However, there is a significant correlation between microvessel density and the development of cervical metastases or recurrence. Previous studies have demonstrated that head and neck cancers are able to induce an angiogenic response in experimental models. This factor shows a strong correlation with regional recurrence. In this study we propose to use angiogenesis as an independent prognostic indicator of recurrence. We evaluated the expression of tumor angiogenesis in OSCC and determinated its possible usefulness as a prognostic factor. Thirty-three cases with diagnosis of OSCC were identified from January 1985 to January 1997 in the Head and Neck Department of the Instituto Nacional de Cancerología in Mexico City. These cases were analyzed retrospectively for a minimum period of six months. All of them received a conventional complete treatment to the primary tumor and lymph node metastasis. Paraffin-embedded tumor specimens were available in all patients. The tumors were scanned and the areas of highest microvessel density (MVD) were immunostained for CD-34 using QBEnd/10 antibody. Statistical analysis included descriptive statistics, Wilcoxon test curves, and Cox's proportional hazards model for multivariate analysis. We identified 33 patients with OSCC, 16 were men and 17 women. The mean age among all patients was 58.9 years old. Based on tumor size 33.3% were T1, 27.3% T2, 12.1% T3, and 27.3% T4. The median microvessel count was 32.5. The mean percentage of MVD was 37 in patients with regional recurrence and in those patients without regional metastasis was 29 (p<0.05). 57.9% of the patients who presented recurrence had vessel counts over the median (p<0.01). In fact, 6 patients (46%) who showed more than 20% of angiogenesis expression and higher MVD presented with recurrence. Only 3 patients (23%) who had less than 20% of angiogenesis expression and lower MVD developed recurrence (p<0.01). Higher MVD was seen with increasing T and N stages; however, it did not show correlation with survival. In this study, angiogenesis expression demonstrated to be an independent factor of recurrence in patients with OSCC. It is suggested that it should be used as an independent prognostic indicator. In concordance with previous reports, we observed a significant correlation between MVD determination and recurrence of the tumor, followed by lymph node metastases and tumor size.

Adult↗
PubMedDate not supplied

The prognostic role of angiogenesis in breast cancer.

Angiogenesis is of key importance in the process of tumour progression in a number of tumour types including breast cancer. Breast cancer angiogenesis has been the most extensively studied and now serves as a paradigm for understanding the biology of angiogenesis and its effects on tumour outcome and patient prognosis. The first study to examine intra-tumoural microvessel density (IMD) immunohistochemically, and relate it to tumour outcome, was carried out by Weidner and colleagues in 1991 using an antibody against factor-8 related antigen as an endothelial marker in a series of breast cancers. They found a near linear relationship between increased microvessel counts and metastasis. This work defined the standard methodology still used today for the morphometric assessment of IMD, such that by evaluating only three so called "hotspot" areas it was possible to determine the metastatic potential of a tumour. The biological rationale behind this was that these highly angiogenic areas were those most likely to be the easiest point of entry for tumour cells into the systemic circulation. Since this initial work there have been many studies which confirm these findings and have related angiogenesis to poor prognosis using a variety of antibodies including those to CD31 and CD34. Angiogenesis is also potentially a unique target for anti-tumour therapy, and much research is being carried out in this area, including blockade of angiogenic signalling pathways and the therapeutic use of antiangiogenic factors.

Breast Neoplasms↗
PubMedDate not supplied

Prognostic significance of angiogenesis in rectal cancer: a morphometric investigation.

BACKGROUND: Neo-angiogenesis is crucial for tumor growth and metastasis and has been proposed as an independent prognostic factor for survival in patients with solid tumors. In this study the quantitative expression of angiogenesis was investigated by direct stereologic assessment of the vascular surface density in rectal carcinoma to determine the possible correlation of angiogenesis with clinicopathological factors and prognosis. PATIENTS AND METHODS: Sections from formalin-fixed paraffin-embedded tissue blocks of 29 primary rectal carcinomas were resected and immunostained for endothelial cell factor-VIII-related antigen. The vascular surface density (VSD), number of vessels per square mm (NVES), maximum NVES (NVESmax) according to the three maximum values of NVES and number of vessels in the unit area (N) were assessed by means of morphometry. The results were related to the main prognostic variables and the survival of patients. RESULTS: There were no significant differences between survivors and non-survivors in terms of the angiogenesis parameters that were investigated. The overall survival rate was not significantly different for sex, age, tumor size and differentiation, extrahepatic metastasis, depth of invasion and the mode of adjuvant therapy. However, a significantly lower overall survival rate was observed in patients with liver metastatic disease (p<0.001), lymph node involvement (p=0.04) and incomplete resection (p<0.001). Multivariate analysis indicated that only the number of vessels in the unit area (HR = 1. 028, p = 0. 04), hepatic metastases (HR=14.94, p=0.007) and type of resection (HR=23.81, p=0.004) predicted overall survival. CONCLUSION: These findings suggest that increased tumoral vascularity, consistent with previous studies, adversely affects survival in rectal cancer patients. Liver metastatic status and completeness of the surgical resection were the most powerful criteria to predict the final outcome of these patients. Thus, neo-angiogenesis is indeed an important and key step in tumorigenesis, but it may not be the single overwhelming factor that determines recurrence and metastasis in rectal carcinoma.

Adult↗
PubMed2002

Angiogenesis and Bcl-2 protein expression in patients with endometrial carcinoma.

Considering the particular importance of angiogenesis and tumor suppressor genes expression in solid tumors, angiogenesis and Bcl-2 protein expression were evaluated in order to specify their role in the biology of endometrial carcinoma. Clinical material comprised 66 patients (postmenopausal, aged 52 to 76 years) with endometrial adenocarcinoma. For evaluation of angiogenesis immunohistochemical method was applied using DAKO EPOS Anti-Human Von Willebrand Factor/HRP antibodies. Morphometric method was applied to count angiogenic points (microvessels + single endothelial cells), using a light microscope with morphometric appliance. Angiogenic points density (APD) was defined as the density of AP per square mm. Immunohistochemical staining for Bcl-2 cytosomic protein expression was performed using MoAb124 (dilution 1:80, Dako A/S, Denmark) monoclonal antibodies. The percentage of 10% positive cells was considered as Bcl-2 positive tissue expression. Positive cytoplasmic reaction of Bcl-2 in 51.3% of patients with Stage I endometrial cancer, and in 23.8% and 0% of patients with II and III FIGO stage, respectively, was observed. No relationship between Bcl-2 tissue cytoplasmatic expression and tumor grade was found. However, an inverse correlation between cytoplasmatic expression of Bcl-2 and FIGO stage was observed. The APD (angiogenic points density) was increasing with the clinical (FIGO) stage of endometrial cancer, but it was not observed in the case of tumor histologic grade. Bcl-2 expression and angiogenesis may be a useful parameter in evaluation of the biology of endometrial adenocarcinoma as the study conducted showed the influence of Bcl-2 protein expression upon angiogenesis.

Adenocarcinoma↗
PubMed2002

Significance of heme oxygenase in prolactin-mediated cell proliferation and angiogenesis in human endothelial cells.

Our objectives were to determine whether heme oxygenase-1 is a second messenger for prolactin-mediated angiogenesis. Endothelial cell proliferation and angiogenesis assay demonstrated that cell number and capillary formation were increased by prolactin (10 and 25 ng/ml). Both protein synthesis and mRNA analysis confirmed that HO-1 expression was induced by prolactin in cultured endothelial cells and occurred in a concentration-dependent manner. Endothelial cells transduced with retrovirus-mediated delivery of HO-1 gene in sense and antisense orientation were used to further determine whether HO-1 overexpression or underexpression modulated prolactin-mediated endothelial cell proliferation and angiogenesis. Incubation of human microvessel endothelial cells transduced with HO-1 in sense orientation resulted in enhancement of prolactin-mediated increase in endothelial cell proliferation and angiogenesis, whereas inhibition of HO-1 by transduction of HO-1 in antisense orientation prevented prolactin increase in endothelial cell proliferation. Similarly, addition of stannic mesoporphyrin, the inhibitor of HO activity, prevented PRL-mediated increase in endothelial cell proliferation. Our results demonstrated for the first time, that prolactin-mediated angiogenesis and cell proliferation was dependent on HO-1 gene expression.

Cell Division↗
PubMed2003

Overexpression of the EGFR/FKBP12/HIF-2alpha pathway identified in childhood astrocytomas by angiogenesis gene profiling.

Intense angiogenesis proliferation, a histopathological hallmark distinguishing malignant from benign astrocytoma, is vital for tumor progression. Thus, identifying and targeting specific pathways that promote malignant astrocytoma-induced angiogenesis could have substantial therapeutic benefit. Expression profiling of 13 childhood astrocytomas to determine the expression pattern of 133 angiogenesis-related genes revealed that 44 (33%) genes were differentially expressed (17 were overexpressed, and 27 were underexpressed) between malignant high-grade astrocytomas (HGAs) and benign low-grade astrocytomas. Hierarchical clustering and principal components analysis using only the 133 angiogenesis-related genes distinguished HGA from low-grade astrocytoma in 100% of the samples analyzed, as did unsupervised analyses using the entire set of 9198 expressed genes represented on the array, indicating that the angiogenesis-related genes were reliable markers of pathological grade. A striking new finding was significant overexpression of hypoxia-inducible transcription factor (HIF)-2alpha as well as high-level expression of FK506-binding protein (FKBP) 12 by HGA. Furthermore, 9 of 21 (43%) genes overexpressed by HGA were HIF/FKBP-associated genes. This group included the epidermal growth factor receptor (EGFR), which promotes HIF synthesis, as well as insulin-like growth factor-binding protein 2 (IGFBP2), a target gene of HIF activity. Differential protein expression of HIF-2alpha was validated in an independent group of 16 astrocytomas (P = 0.02). We conclude that the EGFR/FKBP12/HIF-2alpha pathway is important in childhood HGA and represents a potential new therapeutic target.

Astrocytoma↗
PubMed2003

[Microvessel density and endothelial area in assessment of angiogenesis in patients with laryngeal cancer].

The growth of solid tumours and the process of metastasis are dependent on the formation of new blood vessels. Indeed, the intensity of angiogenesis has been shown to be increase in various human tumours. The main aim of this work was the assessment of angiogenesis intensity (AI) in patients with laryngeal cancer using two methods: microvessels density (MVD) and microvessels area (MVA). The group of 151 patients with laryngeal cancer, surgically treated with minimum 5 years observation, was multi-variously analysed. Paraffin--embedded tissue sections from each case were stained with a monoclonal antibody raised against FVIII and CD34 antigens. Intensity of angiogenesis (IA) was measured as microvessels density (MVD) and microvessels area (MVA) by mean of computer image analysis. There were statistically significant correlation between IA measured as MVD using CD34 and tumour size and nodal metastasis. IA described as MVA correlated with: staging, tumour size, nodal recurrences and metastasis. IA measured as MVD after using anti-FVIII correlated with tumour size and nodal metastasis. MVA correlated with staging and nodal recurrences. Overall survival was related to IA measured as MVD using anti-CD34 and anti-FVIII. Disease-free survival was related to IA measured as MVD using anti-VIII. Intensity of angiogenesis has prognostic value in patients with laryngeal cancer. Both methods: microvessels density and microvessels area seems to have similar value in assessment of angiogenesis intensity.

Adult↗
PubMed2003

Heavy ion irradiation inhibits in vitro angiogenesis even at sublethal dose.

Angiogenesis is essential for tumor growth and metastasis. Because endothelial cells are genetically stable, they rarely acquire resistance to anticancer modalities, and could, thus, be a suitable target for radiation therapy. Heavy ion radiation therapy has attracted attention as an effective modality for cancer therapy because of its highly lethal effects, but the effects of heavy ion irradiation on in vitro cell function associated with angiogenesis have not been reported. Our study found that in vitro angiogenesis was inhibited by high linear energy transfer carbon ion irradiation even at sublethal dose (0.1 Gy). ECV304 and HUVEC human umbilical vascular endothelial cells were irradiated with 290 MeV carbon ion beams of approximately 110 keV/ micro m or 4 MV X-ray of approximately 1 keV/ micro m. Their adhesiveness and migration to vitronectin or osteopontin were inhibited, and capillary-like tube structures in three-dimensional culture were destroyed after carbon ion irradiation concomitant with the inhibition of matrix metalloproteinase-2 activity, down-regulation of alphaVbeta3 integrin, which is one of the adhesion molecules, slight up-regulation of membrane type1- matrix metalloproteinase, and significant up-regulation of tissue inhibitor of metalloproteinase-2. On the other hand, sublethal X-ray irradiation promoted migration of endothelial cells, and the capillary-like tube structure in three-dimensional culture progressed even after 16 Gy irradiation. These results provide an implication that heavy ion beam therapy could be superior to conventional photon beam therapy in preventive effects on in vitro angiogenesis even at sublethal dose, and might inhibit angiogenesis in vivo.

Capillaries↗
PubMed2003

Angiogenic and angiostatic factors in the molecular control of angiogenesis.

The vascular system that ensures an adequate blood flow is required to provide the cells with sufficient supply of nutrients and oxygen. Two different mechanisms of the formation of new vessels can be distinguished: vasculogenesis, the formation of the first primitive vascular plexus de novo and angiogenesis, the formation of new vessels from preexisting ones. Both processes are regulated by a delicate balance of pro- and anti-angiogenic factors. Physiologically, angiostatic mediators outweigh the angiogenic molecules and angiogenesis does not occur. Under certain conditions such as tumor formation or wound healing, the positive regulators of angiogenesis predominate and the endothelium becomes activated. Angiogenesis is initiated by vasodilatation and an increased permeability. After destabilization of the vessel wall, endothelial cells proliferate, migrate and form a tube, which is finally stabilized by pericytes and smooth muscle cells. Numerous soluble growth factors and inhibitors, cytokines and proteases as well as extracellular matrix proteins and adhesion molecules strictly control this multi-step process. The properties and interactions of angiogenic molecules such as VEGFs, FGFs, angiopoietins, PDGF, angiogenin, angiotropin, HGF, CXC chemokines with ELR motif, PECAM-1, integrins and VE-cadherin as well as angiostatic key players such as angiostatin, endostatin, thrombospondin, CXC chemokines without ELR motif, PEDF are discussed in this review with respect to their molecular impact on angiogenesis.

Angiopoietins↗
PubMed2003

CT imaging of angiogenesis.

Tumor angiogenesis has significant implications in the diagnosis and treatment of various solid tumors. With the advent of fast, multi-slice CT scanners, CT imaging techniques capable of qualitative and quantitative analysis of tumor angiogenesis have been the subject of extensive investigation in the past 2 decades. The fundamental bases for CT imaging of angiogenesis are both the transport by blood flow of intravenously administered iodinated contrast material to tissue and the exchange by diffusion of these contrast molecules between the intravascular space and the extravascular interstitial space. With current fast CT scanners both tissue and vascular enhancement can be measured and traced over time at small time intervals to allow detailed modeling of the distribution of contrast agent in tissue. Both compartmental and distributed parameter models for contrast transport and exchange have been developed to quantify from the CT data the following angiogenesis related parameters: tissue blood flow, blood volume, mean transit time, contrast arrival time, capillary permeability surface area product and hepatic arterial fraction in case of the liver. This review addresses the following aspects of CT imaging of angiogenesis: 1) basic concepts related to the understanding of both compartmental and distributed parameter models; 2) comparison between both types of models; 3) practical issues with respect to the measurement of the arterial input function, which is required for the solution of both types of models; and, 4) illustration of the application of a distributed parameter model, the Johnson and Wilson model, in a number of experimental studies.

Angiography↗
PubMed2003

Angiogenesis of prostate cancer and antiangiogenic therapy.

Tumor-associated angiogenesis refers to the growth of new vessels toward and within the tumor. Several studies have revealed that increasing intratumoral microvessel density, a major of tumor-associated angiogenesis, correlates with greater aggressiveness of prostate cancer. Angiogenesis consists of multiple, sequential, and interdependent steps dependent on the local balance of proangiogenic and antiangiogenic molecules Many proangiogenic and antiangiogenic molecules have been demonstrated to regulate growth and metastasis of prostate cancer. As tumor-associated angiogenesis is a crucial step in the process of prostate cancer development, inhibition of tumor neovascularization, and/or destruction of tumor vasculature (antiangiogenic therapy) may maintain the tumors in a dormant state or, perhaps in combination with cytotoxic therapies, potentiate shrinkage of tumors. Recently, therapeutic agents targeting the receptors of proangiogenic molecules and their signal transduction cascade have been developed. In this article, the role of angiogenic molecules in prostate cancer biology, and the application of angiogenesis inhibition to therapeutics for prostate cancer are reviewed.

Angiogenic Proteins↗
PubMed2003

Integrins and angiogenesis: unlocking the route to gene therapy.

Angiogenesis is defined as the process of vascularization of a tissue, involving the development of new capillary blood vessels. Both the induction and inhibition of this process can have therapeutic benefits in various pathological conditions. Integrins are a structurally elaborate family of adhesion molecules; they participate in a wide range of biological processes, including angiogenesis. Endothelial cells are intimately involved in angiogenesis and are thought to mediate this function partially through the integrins on their cell membrane, which regulate cell-cell and cell-matrix contacts. Extensive research into elucidating the mechanisms involved in the angiogenesis process have led to the discovery of a growing number of genes encoding pro- and anti-angiogenic proteins. A variety of gene therapy approaches have been used to deliver many of these genes to induce or inhibit the angiogenesis process with varying levels of success. This review investigates whether targeting gene therapy vectors to integrin receptors found on endothelial cells is a viable means to improve the efficiency of the gene transfer process.

Adenoviridae↗
PubMed2004

Model of angiogenesis in mice with severe combined immunodeficiency (SCID) and xenoengrafted with Epstein-Barr virus-transformed B cells.

Xenoengraftment of human cells in mice with severe combined immunodeficiency (SCID) has been used as a model system to study the mechanisms of B-cell lymphomagenesis. In the study reported here, we determined that SCID mice can also be used as a model to study angiogenesis in B-cell lymphomas. The C.B-17 scid/scid mice were xenotransplanted with Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCL), and we determined whether CD31, a marker found on endothelial cells, was detected in the human B-cell lymphomas that developed in these mice. Microvessel formation was identified by use of immunohistochemical staining for CD31. To assess possible mechanisms of angiogenic stimulus, we analyzed the expression of interleukin 8 (IL-8), a chemokine documented to promote angiogenesis, in non-small-cell lung cancer and bronchogenic carcinomas. We observed that a panel of LCL and LCL-lymphomas expressed IL-8 mRNA and protein. Neutralization of IL-8, however, did not inhibit lymphomagenesis, suggesting that IL-8 is not essential for angiogenesis in this model. To examine other parameters of angiogenesis, we identified expression of vascular endothelial growth factor in the lymphomas. These data suggest that angiogenesis accompanies EBV-associated B-cell lymphoma development, but IL-8 is not essential for this process. Thus, the SCID mouse model is amenable to testing of anti-angiogenic factors.

Animals↗
PubMed2004

Quantitation of angiogenesis and its correlation with vascular endothelial growth factor expression in astrocytic tumors.

OBJECTIVE: To quantitate tumor angiogenesis by establishing intratumoral microvessel density (IMD), to study vascular endothelial growth factor (VEGF) expression in different grades of astrocytomas and to correlate VEGF expression with tumor angiogenesis. STUDY DESIGN: Forty cases of astrocytic neoplasms (10 of each grade) were assessed for tumor angiogenesis and VEGF expression. The panendothelial marker CD31 was used to highlight microvessels. Tumor angiogenesis was quantitated as IMD count per square millimeter in areas of high vascularity, or "hot spots," using an image analyzer. VEGF expression was studied in sections of the tumors. IMD counts per square millimeter and VEGF expression were correlated with histologic grade. The angiogenic potential of tumors as reflected by IMD counts per square millimeter was correlated with the intensity of VEGF expression. RESULTS: Vascular proliferation in high grade gliomas was significantly higher as compared to that in low grade gliomas. IMD count per square millimeter revealed a positive correlation with histologic grade in high grade gliomas. Pilocytic astrocytoma and low grade astrocytoma as a group had comparable IMD counts per square millimeter. VEGF expression paralleled IMD counts in rare high grade gliomas only. CONCLUSION: Malignant progression in astrocytoma is heralded and accompanied by increased angiogenesis. VEGF is an important angiogenic factor in high grade gliomas since its expression parallels the increased IMD counts in these tumors. In contrast, in low grade gliomas, angiogenic factors other than VEGF may contribute to vascular proliferation. The results emphasize the role of antiangiogenic therapy as an optimal tool in therapeutic strategies as they become available.

Astrocytoma↗
PubMed2004

[Angiogenesis in the female reproductive processes].

Angiogenesis or the formation of new vessels out of pre-existing capillaries is a sequence of events that is fundamental to physiology of the female reproductive tract and also pathologic processes such as ovarian hyperstimulation syndrome. Many factors include vascular endothelial growth factor (VEGF), angiopoietins and others involved in the regulation of angiogenesis have been identified. There are some endocrine control mechanisms, which stimulate or inhibit the angiogenesis. The studies indicate that the normal processes of folliculogenesis, ovulation and corpus luteum function in the ovary and the control of menstruation and implantation in the endometrium are profoundly dependent on the angiogenesis. The rapid, controlled and cyclical nature of angiogenesis in the female reproductive tract suggests that interference with this process should provide a novel approach to manipulation of reproductive function.

Angiopoietins↗
PubMed2005

[Gene expression profiling of microvascular endothelial cells during capillary morphogenesis in an in vitro model of angiogenesis].

OBJECTIVE: To globally compare the gene expression profiles during the capillary morphogenesis of human microvascular endothelial cells (HMVECs) in an in vitro angiogenesis system with Affymetrix oligonucleotide array. METHODS: A microcarrier-based in vitro angiogenesis system was developed, in which endothelial cells (ECs) migrated into the matrix, proliferated, and formed capillary sprouts. The sprouts elongated, branched and formed network. The total RNA samples from the HMVECs at the selected time points (0.5 h, 24 h, and 72 h) during the capillary morphogenesis were used for microarray analyses, and the data were processed with the software provided by the manufactory. The expression patterns of some genes were validated and confirmed by Semi-quantitative RT-PCR. The regulated genes were grouped based on their molecular functions and expression patterns, and among them the expression of chemokines/chemokine receptors were specially examined and their functional implications were analyzed. RESULTS: About 1500 genes were found up- or down- regulated 2-folds or above detected by the arrays, and among them, about 400 genes regulated 3-folds or above. The regulated genes could be grouped into categories based on their molecular functions such as growth factor and receptor, cell proliferation, extracellular matrix, cell cycle and apoptosis, signaling molecule and transcription factor, and so on, using the Gene Ontology Mining Tool in The NetAffx Analysis Center. The regulated genes were also clustered into six groups based on their patterns of expression. As for chemokines, the CCL2/MCP-1, CCL5/RANTES and CX3CL1 were identified to be specially upregulated at 24 h time point when the sprouting characterized the morphological change. It was thus suggested that they might exert crucial roles at the early stage of angiogenesis. CONCLUSIONS: Based on our angiogenesis model, and by oligonucleotide arrays, the present study demonstrates global profiles of the gene expression during endothelial capillary morphogenesis, and the results provide us much information about the molecular mechanisms of angiogenesis, with which further evaluation of individual genes can be encouraged.

Capillaries↗