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PubMed2001

Overview of angiogenesis: Biologic implications for antiangiogenic therapy.

Tumor angiogenesis is essential for the growth of primary and metastatic tumors. This process requires the coordinated activities of multiple factors and cell types. For tumors to develop a neovascular blood supply, tumor cells and host cells must secrete proangiogenic factors that offset the activities of inhibitory angiogenic factors. In addition, the newly derived tumor endothelium must respond to signals in the microenvironment to survive under conditions such as hypoxia and acidity. Moreover, because the process of angiogenesis is regulated by redundant factors and pathways, inhibition of any single pathway is likely to select for cells whose angiogenesis is driven by other factors. Because antiangiogenic therapy is unlikely to induce tumor regression, the criteria for efficacy must be evaluated by means other than the standard criteria used to evaluate cytotoxic chemotherapy. Understanding the basic principles that drive tumor angiogenesis will lead to the development of therapies that will likely prolong survival without the toxicity associated with standard chemotherapy.

Angiogenesis Inducing Agents↗
PubMed2002

Principals of neovascularization for tissue engineering.

The goals in tissue engineering include the replacement of damaged, injured or missing body tissues with biological compatible substitutes such as bioengineered tissues. However, due to an initial mass loss after implantation, improved vascularization of the regenerated tissue is essential. Recent advances in understanding the process of blood vessel growth has offered significant tools for therapeutic neovascularization. Several angiogenic growth factors including vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (bFGF) were used for vascularization of ischemic tissues. Three approaches have been used for vascularization of bioengineered tissue: incorporation of angiogenic factors in the bioengineered tissue, seeding endothelial cells with other cell types and prevascularization of matrices prior to cell seeding. This paper reviews the process of blood vessel growth and tissue vascularization, and discuss strategies for efficient vascularization of engineered tissues.

Animals↗
PubMed2002

Intussusceptive angiogenesis--the alternative to capillary sprouting.

In contrast to sprouting angiogenesis, which is a well established mode of new blood vessel formation, intussusceptive angiogenesis (IA) is a relatively new concept in vascular biology. It was first discovered in the lung as a means of capillary network growth (intussusceptive microvascular growth). The mechanism consists in the repeated insertion of new slender transcapillary tissue pillars, which subsequently increase in size, thus allowing the capillary network to grow in itself (i.e., by intussusception). It could be shown that IA was present in all organs and species investigated so far, so that it appears to be an ubiquitous phenomenon in vertebrates at least. It was not a surprise therefore to find that IA also played a role in tumour vascularisation. Morphological analysis has yet brought evidence for 6 different modes of pillar formation. They all have in common that, at one time, two endothelial leaflets (e.g. of opposite capillary walls) come into close contact, form new junctional complexes, then thin out to finally give way to the invading interstitial tissue, particularly to fibroblasts, myofibroblasts and pericytes. Once such a transcapillary pillar is formed, it can subsequently grow to the size of a normal intercapillary mesh. The addition of collagen fibrils to the pillar core will stabilize the pillar mechanically. Recent observations allowed to extend the IA concept further: The same structural mechanism of intussusceptive pillar formation was shown to contribute also to the formation of vascular trees (arborisation) and to be involved in vascular remodeling. Although numerous growth factors and receptors have already been suggested as being active in IA, very few hard facts are at present available which would allow to get a comprehensive view of IA regulation.

Animals↗
PubMed2003

Characterisation and quantification of angiogenesis in beta-tricalcium phosphate implants by immunohistochemistry and transmission electron microscopy.

The aim of this study is the histological characterisation of angiogenesis in a macroporous biomaterial with quantification techniques used in oncology. Porous tricalcium phosphate implants were seated in the tibias of 12 rabbits. This work allows (1) morphological study with photonic microscopy, transmission electron microscopic and immunohistochemistry labelling for (2) quantification of vascularisation using anti-CD31 monoclonal antibody (3) quantification of proliferation using anti-PCNA polyclonal antibody (4) study of two angiogenic growth factors: VEGF and FGF-2. Quantification of angiogenesis revealed an outbreak kinetic with early vascular growth in first several days and a second growth phase after 4 weeks. This study reveals in macropores many isolated cells without adjacent vascular lumen, with endothelial phenotype. Expression of angiogenic growth factors reveals that all endothelial cells were VEGF-negative throughout the test period. FGF-2 expression by endothelial cells began 2 weeks post-implantation. Osteoblasts strongly expressed two markers throughout the test period. Furthermore, the procedure described here can be used to compare angiogenesis in different biomaterials or in the same biomaterial with the influence of macroporosities.

Animals↗
PubMed2000

VPF/VEGF and the angiogenic response.

Vasculogenesis, the generation of new blood vessels de novo, and angiogenesis, the formation of new blood vessels from preexisting vessels, are mediated by a number of cytokines and growth factors among which vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is one of the most important. VPF/VEGF is secreted by many tumor cells, at sites of wound healing and chronic inflammation, and in physiological angiogenesis as in corpus luteum formation. VPF/VEGF is a multifunctional cytokine that interacts with two high affinity tyrosine kinase receptors that are selectively expressed on vascular endothelium. This interaction triggers an angiogenic cascade whose steps, among others, include increased microvascular permeability, leading to deposition of a pro-angiogenic extracellular fibrin matrix, and the formation of mother/daughter vessels.

Animals↗
PubMed2000

Molecular mechanism of angiogenesis transcription factors and their therapeutic relevance.

Controlling angiogenesis, either positively or negatively, is considered to be useful for the treatment of various diseases. Angiogenesis primarily depends on the phenotypic changes of vascular endothelial cells (ECs). Various genes are expressed in ECs during angiogenesis, and thus, understanding of the transcriptional control of these genes in ECs is very important. This review focuses on transcription factors that may play important roles in angiogenesis.

Animals↗
PubMed1997

Vascular endothelial growth factor mediates reactive angiogenesis in the postnatal developing brain.

Although chronic sublethal hypoxia has been shown to promote angiogenesis in the developing brain, the pathogenesis of this response is unknown. We hypothesized that this response may be mediated in part by vascular endothelial growth factor (VEGF). We reared newborn rats (P3) in a chamber with FIO2 of 9.5 +/- 1% (exposed, E). At P33, the animals were removed from the chamber and the brains prepared for immunohistochemistry, mRNA extraction, or horseradish peroxidase (HRP) permeability studies. We also isolated beagle brain germinal matrix endothelial cells from PND 1 beagle pups and placed them in three-dimensional (3-D) coculture with PND 1 rat forebrain astrocytes. Cultures were grown for 6 days in 11% O2 and compared to control 3-D cocultures. When compared to age-matched controls, the experimental rats had significantly increased cortical vascular density (vessels/mm2: 518 +/- 18 vs. 400 +/- 15, P = 0.025). HRP studies demonstrated significantly increased permeability in all cortical vessels examined in experimental rats compared to controls. Compared to controls, VEGF mRNA from hypoxic pups was increased 2.4 times, and immunohistochemical studies of VEGF protein confirmed this finding. Similarly, when compared to controls, hypoxic cocultures of brain microvascular endothelial cells and astrocytes demonstrated significant increase in tubelike structures representing in vitro angiogenesis. Additionally, astrocyte VEGF protein levels increased 4.4-fold in hypoxic compared to control astrocyte cultures and VEGF protein levels increased 1.7-fold in hypoxic compared to control cocultures. Finally, addition of VEGF (10 ng/ml culture medium) to BBMEC alone in 3-D culture elicited not only significant proliferation (P = 0.001) but also increased tube formation. These data demonstrate that the developing brain responds to chronic sublethal hypoxia with increases in permeability and angiogenesis and suggest that VEGF mediates this response.

Animals↗
PubMed2000

The thin red line: angiogenesis in normal and malignant hematopoiesis.

This review describes the current knowledge about cell subsets involved in vasculogenesis (i.e., differentiation of endothelial cells from mesodermal precursors) and angiogenesis (i.e., blood vessel generation from pre-existing vessels), together with recent findings about angiogenesis and antiangiogenic therapies in hematopoietic malignancies such as leukemia, lymphoma, myeloma, and myelodysplastic syndromes.

Animals↗
PubMed2002

Novel benzimidazole derivatives selectively inhibit endothelial cell growth and suppress angiogenesis in vitro and in vivo.

We discovered a novel benzimidazole derivative, named compound (comp.) 1, with unique antiangiogenic characteristics. Comp.1 cytostatically inhibited the vascular endothelial growth factor- and basic fibroblast growth factor-induced growth of endothelial cells (50% inhibitory concentration: 29-79 nM) without a cytotoxic phase, but did not affect the growth of other types of cells up to 90 microM. Comp.1 also inhibited the tube formation derived from a rat aorta fragment, but the oral (p.o.) treatment of comp.1 (46 mg/kg, administered twice daily (b.i.d.)) did not inhibit aniogenesis in a mouse sponge model. Comp.8, an analogue of comp.1, showed a specific inhibitory effect on endothelial cell growth. Comp.8 also suppressed angiogenesis (15 mg/kg, b.i.d., p.o., 70% inhibition) in the sponge model without body weight loss.

Animals↗
PubMed2000

Experimental models of growth factor-mediated angiogenesis and blood-retinal barrier breakdown.

Following chronic ischemia, vascular endothelial growth factor (VEGF) is induced primarily in the ganglion cell layer of the retina. This often results in neovascularization (NV) that originates from the vascular bed closest to the ganglion cell layer. To study the effects of VEGF, independent lines of transgenic mice that express VEGF in the lens and in the retina have been generated. Expression in the lens results in excessive proliferation and accumulation of angioblasts and endothelial cells in proximity to the lens. However, VEGF expression is not sufficient to direct blood vessel organization or maturation in the prenatal mouse. Abnormal vessels do form on the retinal surface, but not until the second postnatal week. In transgenic mice expressing VEGF in the photoreceptors, NV originates from the deep capillary bed--the vascular bed closest to the photoreceptors. NV is accompanied by localized blood-retinal barrier breakdown. NV is also induced in PDGF-B transgenic mice. PDGF-B expression in the lens occurs prenatally and, during this time, mainly affects the perilenticular vessels. Postnatally, transgenic mice expressing PDGF-B in the lens or photoreceptors show a similar phenotype. In both models, a highly vascularized cell mass containing endothelial cells, pericytes, and glia forms in the superficial retina, and the formation of the deep capillary bed is inhibited. The phenotype suggests that an additional factor is necessary for the maturation and penetration of vascular endothelial cells into the retina to form the deep capillary bed.

Animals↗
PubMed2000

Thrombin peptide, TP508, stimulates angiogenic responses in animal models of dermal wound healing, in chick chorioallantoic membranes, and in cultured human aortic and microvascular endothelial cells.

The alpha-thrombin peptide, TP508, accelerates the healing of full-thickness wounds in both normal and ischemic skin. In wounds treated with TP508, a pattern of increased vascularization is consistently observed both grossly and microscopically when compared to wounds treated with saline. One possible mechanism by which the peptide accelerates wound healing is by promoting revascularization of granulation tissue at the injured site. To evaluate the angiogenic potential of TP508, the peptide was tested in the chick embryo chorioallantoic membrane (CAM), where it increased the density and size of CAM blood vessels relative to controls. Additionally, TP508 stimulated chemokinesis and chemotaxis in a dose-dependent fashion in cultured human aortic and human microvascular endothelial cells. Taken together, these in vivo and in vitro data support an angiogenic role for TP508 in wound healing. A working model is presented to explain how this 23-amino-acid peptide, which lacks proteolytic activity, is generated during wound healing and contributes to the nonproteolytic functions associated with alpha-thrombin during tissue repair.

Allantois↗
PubMed2002

Redox signaling in vascular angiogenesis.

Angiogenesis is thought to be regulated by several growth factors (EGF, TGF-alpha, beta-FGF, VEGF). Induction of these angiogenic factors is triggered by various stresses. For instance, tissue hypoxia exerts its pro-angiogenic action through various angiogenic factors, the most notable being vascular endothelial growth factor, which has been mainly associated with initiating the process of angiogenesis through the recruitment and proliferation of endothelial cells. Recently, reactive oxygen species (ROS) have been found to stimulate angiogenic response in the ischemic reperfused hearts. Short exposure to hypoxia/reoxygenation, either directly or indirectly, produces ROS that induce oxidative stress which is associated with angiogenesis or neovascularization. ROS can cause tissue injury in one hand and promote tissue repair in another hand by promoting angiogenesis. It thus appears that after causing injury to the cells, ROS promptly initiate the tissue repair process by triggering angiogenic response.

Animals↗
PubMed1995

Angiogenic activity in normal and dysfunctional uterine bleeding human endometrium; as measured by the chick chorioallantoic membrane assay.

The modified chick chorioallantoic membrane assay was used to measure the angiogenic activity of whole human endometrium, endometrial gland and endometrial stromal cell preparations. Specimens were studied from normal subjects and from those suffering from dysfunctional uterine bleeding. This was done in order to investigate possible sites of angiogenic factor synthesis in endometrium. Significant angiogenic activity was demonstrated in all three sites and was present in all phases of the cycle except for the late secretory phase specimens. In the late secretory phase, compared to the controls, there was no significant angiogenic activity in the whole endometrial, endometrial gland nor endometrial stromal cell preparations. There were no differences in angiogenic activities between the various phases studied apart from a significant decrease in angiogenic activity for the endometrial gland cell preparations between the midsecretory phase and the late secretory phase. This study suggests than human endometrium produces local angiogenic factors throughout the menstrual cycle and that these factors may decrease towards the end of the cycle. It has been suggested that dysfunctional uterine bleeding may be due to disturbances in local angiogenic factors produced in the endometrium. This study found no significant differences in angiogenic activities between normal endometrium and dysfunctional endometrium. This suggests that dysfunctional uterine bleeding may not be due to disturbances in local angiogenic factors.

Animals↗
PubMed2001

Adhesion events in angiogenesis.

Recent work from several laboratories indicates that the coordination of endothelial cell adhesion events with growth factor receptor inputs regulates endothelial cell responses during angiogenesis. Analyses of the signaling pathways downstream of integrins, cadherins and growth-factor receptors are providing an insight into the molecular basis of known anti-angiogenic strategies, as well as into the design of novel therapies.

Angiogenesis Inhibitors↗