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Results for “Neovascularization, Pathologic”

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PubMed1992

Suramin prevents neovascularisation and tumour growth through blocking of basic fibroblast growth factor activity.

Inhibition of angiogenesis through blocking of growth factors involved in this process could be a novel therapeutic approach in several important pathologies, neoplasia among them. Suramin has recently been described to possess antineoplastic activity in animals and humans, and it has been proposed that an important role in this activity is played by antagonism of growth factors and especially bFGF. To investigate this hypothesis in vivo, we used gelatin sponges loaded with bFGF and implanted subcutaneously in mice. Suramin showed an inhibitory activity on bFGF-induced angiogenesis, whereas it was inactive in the case of heparin-complexed bFGF. Suramin was also studied in an in vivo model of tumour-induced angiogenesis using the murine M5076 reticulosarcoma, a tumour producing significant levels of bFGF. Suramin was able to reduce tumour growth and tumour induced angiogenesis, and exogenous administration of bFGF countered suramin effects.

Animals↗

PubMed1987

Angioinvasive plasma cell granulomas of the lung.

A series of eight plasma cell granulomas of the lung were examined. Their clinical, pathologic, and immunohistochemical characteristics as well as the ultrastructural features of one case are in agreement with those found in the literature. One patient died after a surgical intervention complicated by invasion of pulmonary veins. This led to a search for vascular injuries in the other cases. On the whole, of eight cases, two showed vascular invasions at a distance, five (including the preceding ones) showed invasion of medium-sized blood vessels in the peripheral parts of the lesion, and three showed older invasions in their center; only two had no vascular lesions. To the authors' knowledge, vascular invasion at a distance has been reported only once to date. An inflammatory origin for these cytologically benign lesions remains possible, although a striking resemblance with intravascular fasciitis can also be shown. These lesions should be treated by radical and precocious surgery.

Adolescent↗

PubMed1995

Assessment of bone formation during osteoneogenesis: a canine model.

Distraction osteoneogenesis, callotasis, has been demonstrated to be an effective means of lengthening long bones. A variation of Ilizarov's technique produces a transport disk from one cut surface of bone within a defect and advances the disk to the opposite surface to close the defect. This process, previously described by Costantino et al. (Arch Otolaryngol Head Neck Surg 1990; 116:535-45), demonstrated bone formation within the distraction site. The precise mechanism of bone formation has not yet been described for the mandible. Four conditioned beagles were studied, with one control dog maintained in neutral fixation and three dogs distracted at 0.25 mm every 8 hours. A two-cm defect was closed, and dogs were kept in fixation for 1 week after closure, after which they were killed. Three sites were evaluated: (1) the distraction seam, (2) the interface of the cortical and distracted bone, and (3) the cortexes at the closed defect. Each site was bisected, and one half was decalcified for immunohistochemical and hematoxylin and eosin pathologic evaluation. The vascular basement membrane was labeled for laminin and type IV collagen. Both of these substances demonstrate the differentiation of the vascular matrix component predisposing primary bone formation. Labels were intense at the distraction seam where intense angiogenesis occurred. No hyalin cartilage was observed at the distraction site, which indicates that the fixation was stable and that ossification occurred primarily without intermediate callous formation. This model demonstrated that osteoclasts within the canine model produce bone through primary bone formation within an angiogenic matrix rich in basement membrane laminin and type IV collagen. Likewise, bone is species specific in mineral composition for dog mandible. Understanding the formation and composition of distracted bone is essential for understanding application of this technique within the clinical setting.

Animals↗

PubMed1994

Microcirculation research, angiogenesis, and microsurgery.

Angiogenesis, the formation of new blood vessels, is essential to a variety of normal and pathologic processes such as wound healing and tumor growth. In microsurgery the development of new vessels between the transferred tissue and the recipient bed is critical to the final outcome of the reconstruction. Several experimental models have been previously developed to study angiogenesis and the effect that new substances have on regulating this process, but they lack the ability to make quantitative measurements. Therefore, we have developed an animal model using the homozygous (hr/hr) hairless mouse ear; by using intravital microscopy and computer-assisted analysis, angiogenesis can be quantitatively measured. Using this model we showed that basic fibroblast growth factor and transforming growth factor beta significantly increased total vessel length by 32% and 63%, respectively, during 20 days following subcutaneous injection. In this paper the importance of angiogenesis research to reconstructive microsurgery is presented and discussed.

Animals↗

PubMed1993

Growth control and morphogenesis in the development and pathology of arteries.

We briefly review and compare the current knowledge of growth mechanisms for the mitogenic response of endothelial cells and smooth-muscle cells to injury. For the endothelium, this focuses on the evidence that growth control involves two components: an endogenous inhibition mechanism, which can be overcome either by fibroblast growth factor (FGF) or by other agents that disrupt cell-cell junctions, and a separate mechanism, which requires FGF to allow cells to respond to a mitogenic effect. The smooth-muscle cell story is more complex; however, there is evidence here as well of an endogenous inhibitory mechanism, which may be overcome by a wide variety of agents. Platelet-derived growth factor, long seen as a major mitogen, does not itself now appear to be a major mitogen in vivo. In contrast, FGF also seems to play a major role in initiating smooth-muscle replication. Other molecules, including angiotensin II, bradykinin, thrombin, and catecholamines, are beginning to appear to play major roles in control of smooth-muscle replication in vivo as well.

Animals↗

PubMedDate not supplied

Angiogenesis under normal and pathological conditions.

Angiogenesis, i.e. the generation of new blood capillaries, occurs in utero (during embryonal and fetal development) and in both physiological and pathological situations during extrauterine life. Several angiogenic factors have now been isolated, including angiogenin, acidic and basic fibroblast growth factors, and alpha and beta transforming growth factors. Their amino acid sequences have been determined and their genes cloned. Other factors await complete characterisation. An account is given of techniques used in the investigation of angiogenesis, both in vivo (transparent chambers; corneal micropockets; implantation on chick chorioallantoic membrane; employment of polymers for the sustained release of angiogenesis factors) and in vitro (cloning and long-term culture of capillary endothelial cells). The angiogenesis induced by solid tumours differs from other forms in that it is not self-limited and continues indefinitely until eradication of the tumour or death of the host. Anti-angiogenic factors have also been identified, particularly a new class of nonglucocorticoid steroids. Their employment in tumour therapy is a possibility, since neoplastic expansion is essentially dependent on angiogenesis.

Angiogenesis Inducing Agents↗

PubMed1994

Molecular mechanisms of developmental and tumor angiogenesis.

Angiogenesis, the sprouting of capillaries from preexisting vessels, is of fundamental importance during embryonic development and is the principal process by which the brain and certain other organs become vascularized. Angiogenesis occurs during embryonic development but is almost absent in adult tissues. Transient and tightly controlled (physiological) angiogenesis in adult tissues occurs during the female reproductive cycle and during wound healing. In contrast, pathological angiogenesis is characterized by the persistent proliferation of endothelial cells, and is a prominent feature of diseases such as proliferative retinopathy, rheumathoid arthritis, and psoriasis. In addition, many tumors are able to attract blood vessels from neighbouring tissues. Tumor-induced angiogenesis requires a constitutive activation of endothelial cells. These endothelial cells dissolve their surrounding extracellular matrix, migrate toward the tumor, proliferate, and form a new vascular network, thus supplying the tumor with nutrients and oxygen and removing waste products. The onset of angiogenesis in human gliomas is characterized by the expression of genes encoding angiogenic growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) in tumor cells, and coordinate induction of genes in endothelial cells which encode the respective growth factor receptors. Developmental and tumor angiogenesis appear to be regulated by a paracrine mechanism involving VEGF and VEGF receptor-1 and -2.

Animals↗

PubMed1994

Vascular permeability factor in brain metastases: correlation with vasogenic brain edema and tumor angiogenesis.

Metastatic brain tumors are almost always associated with vasogenic brain edema, which in turn plays a pivotal role in the evolution of neurological morbidity associated with these lesions. Attention has recently focused on a group of proteinaceous vascular permeability factors (VPF's) that are capable of inducing angiogenesis and promoting increased capillary permeability. To test the hypothesis that metastatic brain tumors expressing VPF's are associated with peritumoral cerebral edema, a rabbit polyclonal immunoglobulin (Ig) G anti-VPF was used to immunostain pathological specimens of metastatic cerebral tumors obtained from 22 patients who underwent surgery at Yale-New Haven Hospital. Magnetic resonance (MR) imaging was used to correlate VPF staining in tumor tissue with the occurrence of peritumoral brain edema. A histological study of the microvasculature was then conducted by immunostaining the specimens for endothelial cell factor VIII surface antigen, using two gliosis specimens as controls. Results revealed 21 of 22 tumors stained positively for VPF's; the negative-VPF tumor was a melanoma that exhibited no peritumoral edema. Twenty of 22 tumors had MR imaging-evident vasogenic edema. The presence and intensity of VPF immunostaining of microvascular features were noted and compared. Factor VIII staining demonstrated tumor vascularity to be most abundant in VPF-rich regions of tumor. The authors therefore report a high correlation between the presence of VPF's and the occurrence of peritumoral brain edema associated with cerebral metastases.

Brain Edema↗

PubMed1992

Magnetic resonance imaging and pathological correlates of meningiomas.

We examined the relationships between specific magnetic resonance imaging features and certain gross and microscopic characteristics of meningiomas, including vascularity, gross texture (consistency), and venous sinus involvement. Magnetic resonance imaging scans, surgery reports, and the histopathological findings of tumors were examined retrospectively in 54 patients. Sinus involvement was accurately predicted on T1-weighted images in 9 of 10 cases (P = 0.001) and tumors with cystic changes in 3 of 3 cases. T1-weighted images were not useful for predicting vascularity unless actual flow voids could be visualized (five of six cases). There was no correlation between T1 signal intensity, tumor consistency, or histological findings. In tumors without detectable vascularity on T1-weighted images, hyperintensity relative to gray matter on T2-weighted images was correlated with increased vascularity (P = 0.004). Tumors with soft consistency (P = 0.007), cellular atypia, invasion, angioblastic, or melanocytic components were also hyperintense, compared with gray matter on T2-weighted images (P = 0.0266). Aggressive meningiomas were found to be more vascular (P = 0.045). No correlation was found between the degree of surrounding edema or contrast enhancement with histopathological findings, vascularity, or consistency.

Brain↗

PubMed1991

Purification and biological properties of vasculotropin, a new angiogenic cytokine.

Angiogenesis is a key step in organ development and remodeling during embryogenesis or tissue regeneration. Some pathological events such as tumor growth or diabetic retinopathy also lead to angiogenesis formation. Several molecules have already been identified as promoting angiogenesis in vivo. Whether their bioactivity is mediated by other angiogenic growth factors or not is still unclear. We identified and purified recently a new angiogenic growth factor. Its unique specificity for vascular endothelial cells led us to provisionally name it vasculotropin (VAS). We describe the biochemical properties of VAS and its biological functions. Structural data showed that VAS is related to the SIS family. In vivo VAS was recognized as an inducer of angiogenesis and vascular permeability. In vitro, despite a moderate action on proliferation, VAS strongly stimulates the cell migration. The screening of the presence of cellular receptors and VAS production showed that the cells which bind VAS do not synthesize it, whereas the cells which synthesize VAS do not bind it. Thus, VAS seems to act through a paracrine pathway. We also present data suggesting that VAS has a lymphokine activity.

Amino Acid Sequence↗

PubMed1990

Endothelial cell growth: biology and pharmacology in relation to angiogenesis.

The vascular system is lined by a monolayer of endothelial cells which proliferate very slowly under normal conditions. The formation of new capillary vessels is associated with some physiological circumstances and several pathological conditions. Angiogenesis requires migration, differentiation and proliferation of endothelial cells. The mechanism of tube formation is still poorly understood. Tumour growth is angiogenesis-dependent and angiogenesis is directly or indirectly induced by the tumour. Induction of angiogenesis is an important step in carcinogenesis and in metastatic development. Angiogenesis is induced during the transition from hyperplasia to neoplasia. Numerous angiogenic factors have been identified, most are mitogenic for endothelial cells and some are only responsible for tube formation. However, it is difficult to recognize which factor is the most important in vivo. Since angiogenesis is necessary for tumour growth, any natural or synthetic antiangiogenic compound may have an antineoplastic potential. Inhibition of tumour angiogenesis under the control of a tumour suppression gene could play an important role. Pharmacological compounds, such as heparin, heparin fragments and corticosteroids, have been shown to be antiangiogenic substances. More recently two new inhibitors of capillary endothelial cell proliferation and/or angiogenesis have been described: they are a cartilage-derived inhibitor and platelet factor 4.

Animals↗

PubMed1994

Selective increase in blood-tumor barrier permeability by calcium antagonists in transplanted rat brain tumors.

To clarify the altered response of calcium antagonists on pathological vessels, we investigated the effect of intracarotid infusion of nifedipine on the blood-brain barrier (BBB) permeability using a rat glioma model. Animals were treated with 0, 0.1, 1, 5, and 10 micrograms/kg/min of intracarotid continuous infusion of nifedipine. 2% Evans blue (EB, 2 ml/kg) was injected intravenously immediately after nifedipine infusion. BBB and blood-tumor barrier (BTB) permeability were evaluated by direct visual and histological observation. During the entire experiment, systemic parameters such as arterial blood pressure and blood analysis were not changed significantly. There was a dose-dependent increase of EB permeability selectively in the tumor tissue without affecting the normal brain. These results indicate that tumor vessels may show an altered response to calcium antagonists. Intracarotid administration of calcium antagonists contribute to a selective enhancement of drug delivery to malignant brain tumors without affecting the normal brain.

Animals↗

PubMed1987

Lymphatics and blood vessels, lymphangiogenesis and hemangiogenesis: from cell biology to clinical medicine.

The past 15 years have witnessed an explosion of knowledge about blood vascular endothelium due in large part to in vitro growth of endothelial cells from both large blood vessels and capillaries. In contrast, little comparable information has accumulated on endothelium of lymphatics, which lie in intimate contact with parenchymal cells and drain excess fluid, macromolecules, particles, and immunocompetent cells in a continuous recirculation between tissues and bloodstream. While structural and functional differences between the two vascular systems have been described in vivo, in tissue sections, and in isolated preparations, similarities are notable in ultra-structure, biochemistry, physiology, and pharmacologic responsiveness, and these may predominate under pathologic conditions. In 1984, three separate groups described in vitro culture of lymphatic endothelial cells from collecting ducts and cavernous lymphangiomas. Lymphatic, like blood vascular, endothelium grows in confluent monolayers, "sprouts", synthesizes Factor VIII-associated antigen and fibronectin, and ultrastructurally shows Weibel-Palade bodies; overlapping intercellular junctions and anchoring filaments typical of lymphatic endothelium are also found. Genetic, congenital, and acquired disorders such as strangulating fetal nuchal cystic hygromas (Down and Turner syndromes), vascular tumors and dysmorphogenesis (Maffucci and Klippel-Trenaunay syndromes), Kaposi's sarcoma, lymphogenous and hematogenous spread of cancer, and parasitic infestations such as filariasis, share overlapping abnormalities in formation, growth, and/or neoplasia of lymphatics and blood vessels. In these and similar clinical disorders, confusion often exists as to the nature of the cell or tissue of origin, and insight into the role and control of hemangiogenesis and lymphangiogenesis is still in its infancy. Nonetheless, with the ever widening array of investigative techniques, it is not only timely but imperative to explore the endothelial biology underlying these inborn and acquired disorders.

Animals↗

PubMed1994

Regional differences in spontaneously occurring angiogenesis in the adult rat mesentery.

Despite intensive study in the area of angiogenesis, relatively little is known about normal angiogenesis in adult animals. Preliminary studies using the Griffonia simplicifolia I (GSI) lectin as a microvascular marker indicated that capillary sprouting occurs in the clear "windows" of normal intact adult rat mesentery. The purpose of this study was to determine whether angiogenesis occurs uniformly within the mesenteric windows and whether maturational age affects the extent of angiogenesis in the absence of any experimental or pathological perturbation. Four groups of female Sprague-Dawley rats were used, "weanling" (4-5 weeks), "juvenile" (6-8 weeks), "young adult" (10-13 weeks), and "adult" (16-20 weeks). Microvessels sprouting into proximal and distal windows were delineated in whole mounts by use of fluorescent derivative of the GSI lectin. Microvascular sprouting, indicating angiogenesis, was found in all age groups, but was most frequent in the windows sampled from the distal region of the small intestine when compared with those from the proximal region. The mean number of microvessels per sample site was significantly higher in the distal windows of adults than in the weanling or juvenile rats. Angiogenesis was found to occur asymmetrically within the individual windows in the two adult groups, with significantly more angiogenesis on the intestinal side compared to that along the portal vessels. We conclude that there is an age-related increase in angiogenesis into the mesenteric windows, and that the intestinal side is more prone to spontaneous angiogenesis than is the portal side.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1995

Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells.

Vascular endothelial growth factor (VEGF) is an endothelial specific angiogenic mitogen secreted from various cell types including tumor cells. Increasing evidence suggests that VEGF is a major regulator of physiological and pathological angiogenesis, and the VEGF/VEGF receptor system has been shown to be necessary for glioma angiogenesis. Hypoxia seems to play a critical role in the induction of VEGF expression during glioma progression. C6 glioma cells provide an in vivo glioma model for the study of tumor angiogenesis, and the expression of VEGF in C6 cells has been shown to be up-regulated by hypoxia in vitro. However, little is known about the molecular mechanism of hypoxic induction of VEGF. Here, we demonstrate that hypoxic induction of VEGF in C6 cells is due to both transcriptional activation and increased stability of mRNA. Nuclear run-on assays revealed a fast and lasting transcriptional activation, whereas the determination of mRNA half-life showed a slower increase of mRNA stability during hypoxia. Reporter gene studies revealed that hypoxia responsive transcription-activating elements were present in the 5'-flanking region of the VEGF gene. These results suggested that several distinct molecular mechanisms were involved in hypoxia-induced gene expression and were activated in a biphasic manner.

Animals↗

PubMed1993

Angiogenic macrophages produce the angiogenic inhibitor thrombospondin 1.

Previous investigations have shown that macrophages play a pivotal role in the induction of angiogenesis in both physiological and pathological settings. This investigation examines the relative production of the angiogenic modulator thrombospondin-1 (TSP1) by activated and nonactivated monocytes and macrophages. TSP1, a multifunctional extracellular matrix molecule, has been reported recently to inhibit angiogenesis both in vitro and in vivo. To examine the relationship between the level of TSP1 production by macrophages and expression of the angiogenic phenotype, murine monocytelike cells (WEHI-3) and human peripheral blood monocytes were each activated in vitro and examined for TSP1 production and angiogenic activity in rat corneal bioassay. Nonangiogenic monocytes produced low levels of TSP1 messenger RNA. Surprisingly, activated, potently angiogenic monocytes and macrophages exhibited as much as a sixfold increase in steady state TSP1 messenger RNA over unstimulated levels. Biosynthetic labeling studies demonstrated that TSP1 protein secretion increased in conjunction with increased TSP1 messenger RNA levels in angiogenic macrophages. The results demonstrate that activated monocytes and macrophages actively produce the angiogenic modulator TSP1 and suggest that TSP1 production may be a component of the angiogenic phenotype. In addition, the data suggest that the ability of macrophages to mediate angiogenesis results from a complex interplay of positive and negative regulators.

Animals↗

PubMed1985

Angiogenesis and its inhibitors.

The hypothesis that solid tumors are angiogenesis-dependent has, in the past decade, generated much new work aimed at understanding the mechanism of angiogenesis itself. Many laboratories in this country and abroad are now studying some aspect of this intriguing problem. Some investigations are focused mainly on tumor angiogenesis, whereas others are centered on angiogenesis that occurs in physiologic situations or that dominates certain non-neoplastic pathologic states. These efforts have brought about [a] the development of bioassays for angiogenesis; [b] the partial purification (and in one case the complete purification) of angiogenic factors from neoplastic and non-neoplastic cells; [c] the development of new polymer technology for the sustained release of these factors and of other macromolecules in vivo; [d] the cloning and long-term culture of capillary endothelial cells; [e] the demonstration of the role of nonendothelial cells, such as mast cells, in modulating angiogenesis; [f] the discovery of angiogenesis inhibitors; and [g] the recent demonstration that certain animal tumors will undergo complete regression when treated by antiangiogenesis alone. The effects of angiogenesis inhibitors provide the most compelling evidence for the role of angiogenesis in tumor growth. That it is now possible not only to inhibit tumor growth but also to eradicate some experimental tumors speaks strongly for a therapeutic approach that may some day be useful in clinical oncology. Conceivably, the original goal to understand the role of angiogenesis in tumor growth will lead to the use of angiogenesis inhibitors in other non-neoplastic diseases.

Animals↗

PubMedDate not supplied

Coronary capillaries during normal and pathological growth.

The adaptive capacity of the myocardium with respect to its capillary concentration and distribution has been measured morphometrically during the hypertrophic growth occurring physologically after birth and as a result of induced overload in the adult. In particular, the growth of the capillary network of the left ventricle was examined in rats from one to 150 days of age and in rats with spontaneous hypertension, aortic stenosis, two-kidney one-clip renal hypertension and myocardial infarction. The following quantitative structural parameters of the capillary microvasculature were analyzed: 1. Capillary luminal volume density; 2. Capillary luminal surface density; 3. The average diffusion distance for oxygen; and 4. The aggregate capillary length in the whole ventricle. The major conclusions of the present study are: 1. The postnatal growth of the heart is characterized by lengthening of the whole capillary network that is linearly related to the aging process; 2. The rate of capillary proliferation, measured by changes in capillary density, is greater in the first month of age; 3. In contrast to postnatal development, lengthening of the capillary microvasculature is not a consistent adaptive mechanism of induced cardiac hypertrophy; 4. Capillary luminal volume and surface densities and the diffusion distance for oxygen are essentially maintained in spontaneous, mechanical and renal hypertension; and 5. Cardiac hypertrophy in acute and healed myocardial infarction results in alterations of the capillary properties implicated in tissue oxygenation that may constitute the morphological counterpart of the greater vulnerability to ischemic episodes of the hypertrophied myocardium after infarction.

Animals↗