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PubMed2004

Nitric oxide modulation of early angiogenesis.

Angiogenesis is the process of new vessel formation from an existing vasculature network. In all but a few circumstances it is tightly controlled and suppressed. Precise understanding of the factors involved in modulation of angiogenesis has significant potential clinical value. One agent believed to play a role in angiogenesis is nitric oxide. However, there remain substantial uncertainties concerning the specifics of this role. The present study was undertaken to better define the role nitric oxide plays in angiogenesis associated with acute wound healing. Muscle biopsies from the pectoralis major of C57B6 mice were embedded in 500 microl of type I collagen matrix, and incubated in the presence of growth medium for 14 days. Treatment wells received L-Arginine (2 mM), L-NAME (300 microM), or SNAP (10-20 microM). Angiogenic response was quantified as the measure of cell migration through the matrix and as the total cells recovered from the matrix. Whole lung specimens and aortic segments served as sources of endothelial and vascular smooth muscle cells respectively for proliferation studies under similar treatment conditions. Nitric oxide was found to exert either a stimulatory or inhibitory effect on angiogenesis and cell proliferation that was subject to the assay system and specific vascular cell types present. These results suggest that the role of nitric oxide in angiogenesis is context dependent.

Analysis of Variance↗
PubMed2003

Expression of angiogenesis- and apoptosis-related genes in chorionic villi derived from recurrent pregnancy loss patients.

Angiogenesis takes place during embryogenesis, characterized by the formation of new blood vessels from pre-existing ones. This biological process is also found in the female reproductive system, wound healing, and cancer development. Apoptosis, programmed cell death, is a physiological process in development, tissue homeostasis, and disease. Apoptosis is a normal event in several reproductive tissues including human placenta. In these studies, we investigated whether aberrant angiogenesis and apoptosis are associated with recurrent pregnancy loss (RPL). We compared the gene expression level for angiogenesis- and apoptosis-related genes in chorionic villi from RPL patients and those from normal controls. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that 7 angiogenesis- and 12 apoptosis-related genes were abnormally expressed in chorionic villi from RPL patients. Angiogenesis-related genes that showed aberrant expression level are matrix metalloproteinase-2 (MMP-2), plasminogen activator inhibitor (PAI), integrin, transforming growth factor-beta (TGF-beta), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and leptin receptor. Expression levels for these genes, except for leptin receptor, showed less in chorionic villi from RPL patients than those from normal controls. In contrast, higher expression levels of 12 apoptosis-related genes (caspase 3, 6, 7, 8, 9, 10, 12, BAD, BAX, BID, Fas, and FasL) were shown in chorionic villi from RPL patients than those from normal controls. Taken all together, it is likely that the lower expression of angiogenesis-related genes and the excessive expression of apoptosis-related genes are associated with RPL.

Abortion, Habitual↗
PubMed1996

Novel synthetic analogs of sialyl Lewis X can inhibit angiogenesis in vitro and in vivo.

Selectins have been shown to play an important role in angiogenesis. We have set out to synthesize multiple analogs of the selectin ligand sialyl Lewis X. We show here that analogs of sialyl Lewis X at concentrations of 50 micrograms/ml or greater significantly inhibited angiogenesis in in vitro assays of endothelial cell migration and proliferation (p < 0.05). These analogs also exerted significant inhibitory effects in in vivo angiogenesis assays using the chick chorioallantoic membrane at doses of 2 mg/chick or greater (p < 0.05). In contrast, the related carbohydrate Lewis X did not inhibit angiogenesis in both in vitro and in vivo assays. These data indicate that angiogenesis can be inhibited specifically by synthetic analogs of sialyl Lewis X. These analogs may potentially be useful in the treatment of angiogenesis-related diseases.

Animals↗
PubMed2002

Angiogenesis induced by the injection of peripheral leukocytes and platelets.

BACKGROUND: Peripheral leukocytes and platelets (LAPs) contain many kinds of cells with the ability to secrete several growth factors and cytokines. We attempted to induce therapeutic angiogenesis by injecting self-LAPs into a rat ischemic hindlimb model. MATERIALS AND METHODS: Supernatants from cultured LAPs were used for the endothelial cell (EC) proliferation assay, and LAPs were used in a cornea model to evaluate angiogenic potency. LAPs were injected directly into the male Dark Agouti rat ischemic hindlimb model, after which a microangiogram was done and the capillary/muscle fiber ratio was examined histologically. ELISA revealed the levels of contributing growth factors and cytokines present in the ischemic muscles. RESULTS: The EC proliferation assay showed that the supernatants of LAPs accelerated proliferation and that the LAPs induced angiogenesis in the cornea model. The microangiograms and histological evaluation revealed that angiogenesis was induced more effectively in the rats injected with LAPs (LAP group) than in the those injected with phosphate-buffered saline (PBS group). The levels of basic fibroblast growth factor (bFGF) in the ischemia, PBS, and LAP groups were significantly increased compared to those in the sham group. The level of interleukin-1beta (IL-1beta) in the LAP group was significantly more elevated than in the other groups. CONCLUSIONS: The injection of self-LAPs induced angiogenesis in a rat ischemic hindlimb model. Ischemia caused an elevation in the level of bFGF and also in IL-1beta derived from LAPs, which contributed to angiogenesis. This is a novel, yet simple and safe method of inducing therapeutic angiogenesis.

Animals↗
PubMed1999

A comparison of two controlled-release delivery systems for the delivery of amiloride to control angiogenesis.

The diuretic amiloride has been reported to inhibit both Na+-H+ antiport and the urokinase-type plasminogen activator. As a consequence of these inhibitions, neovascularization may also be inhibited. We hypothesized that if amiloride could be effectively delivered in a site-specific manner, a system might be developed that could inhibit localized angiogenesis. In order to evaluate this possibility we conducted a study that compared two different controlled-release systems into which amiloride had been incorporated. The effectiveness of amiloride release from each delivery system was determined by quantitating angiogenic patterns in a chick chorioallantoic membrane (CAM) system using a fractal analysis software program. The two delivery systems compared were sucrose acetate isobutyrate (SAIB) and calcium alginate. Initial HPLC laboratory tests confirmed that amiloride could be released from both SAIB and calcium alginate in vitro in a sustained manner for 72 h. The CAM studies confirmed that neither SAIB nor calcium alginate alone promoted or inhibited angiogenesis when compared to nontreated controls. The release of amiloride from each delivery vehicle resulted in a significant (P < 0.05) inhibition of angiogenesis following both 24 and 48 h of release compared to controls. There was no difference in inhibition of angiogenesis, however, when comparing SAIB + amiloride treated CAMs with calcium alginate + amiloride treated CAMs. These data suggest that both SAIB and calcium alginate may be useful delivery vehicles for the localized application of amiloride to control angiogenesis. Such a system could potentially control tumor angiogenesis without systemic effects.

Alginates↗
PubMed2000

Nitric oxide induces angiogenesis and upregulates alpha(v)beta(3) integrin expression on endothelial cells.

Nitric oxide (NO) has been implicated as a mediator of angiogenesis. However, its precise role in angiogenesis and its mechanism of action have not been established. We performed in vivo and in vitro angiogenesis assays using NO donor S-nitroso-N-acetylpenicillamine (SNAP) and NO synthase inhibitor N-iminoethyl-l-ornithine (L-NIO). SNAP significantly increased and L-NIO significantly suppressed capillary ingrowth into subcutaneously implanted Matrigel plugs in mice. For the in vitro angiogenesis assay, human umbilical vein endothelial cells (HUVECs) (4 x 10(4) cells/well) were treated with placebo, SNAP (100 microM), or L-NIO (100 microM) and cultured on Matrigel for 18 h. The typical capillary networks formed on Matrigel by HUVECs as a result of cell migration and differentiation were quantified by computer-assisted image analysis as a measure of angiogenesis. Treatment of HUVECs with SNAP significantly increased the capillary network area compared with control, 8701 +/- 693 vs 6258 +/- 622 area units (P < 0.05), whereas L-NIO significantly decreased the capillary area (4540 +/- 342, P < 0.05). Furthermore, we have shown with a blocking monoclonal antibody that formation of capillary networks on Matrigel is mediated by the functional expression of the alpha(v)beta(3) integrin, which plays a role in facilitating endothelial cell adhesion to basement membrane matrix and endothelial cell migration. After an 18-h culture, flow cytometry revealed that SNAP significantly upregulated and L-NIO significantly downregulated in a concentration-dependent manner alpha(v)beta(3) integrin expression on endothelial cells. In conclusion, NO induces angiogenesis in vivo and in vitro by promoting endothelial cell migration and differentiation into capillaries. One possible mechanism might involve the upregulation of alpha(v)beta(3) integrin on endothelial cells, a critical mediator of cell-matrix adhesion and migration.

Animals↗
PubMed1996

Regulation of angiogenesis by SPARC and angiostatin: implications for tumor cell biology.

The formation of blood vessels through endothelial cell proliferation from extant vasculature (angiogenesis) is a prerequisite for the remodeling, regeneration and repair of tissue. In pathological processes, angiogenesis is a major limiting step in tumor growth and is necessary for tumor formation at metastatic sites. Angiogenesis consists of a sequence of events that include (i) dissolution of the basement membrane, (ii) migration and (iii) proliferation of endothelial cells, (iv) formation of the vascular loop, and (v) formation of a new basement membrane. A variety of factors control and regulate these multiple steps during which the endothelium gives rise to new vessels. Growth factors such as vascular endothelial growth factor or platelet-derived growth factor act directly on endothelial cells and/or activate inflammatory cells (monocytes and T lymphocytes) which in turn synthesize angiogenic factors. SPARC (Secreted Protein Acidic and Rich in Cytsteine), in conjunction with other known angiogenic factors, might act pleiotropically during angiogenesis. Recently, angiostatin, a novel endogenous inhibitor of metastasis, has been reported. This protein, a cleavage product of plasminogen, most likely acts through inhibition of angiogenesis. Current research is focused on the angiogenic and antiangiogenic properties of SPARC and angiostatin and will provide us with a better understanding of how these important factors regulate angiogenesis.

Amino Acid Sequence↗
PubMed1995

The tetracycline analogs minocycline and doxycycline inhibit angiogenesis in vitro by a non-metalloproteinase-dependent mechanism.

The tetracycline analogs minocycline and doxycycline are inhibitors of metalloproteinases (MMPs) and have been shown to inhibit angiogenesis in vivo. To further study the mechanism of action of these compounds we tested them in an in vitro model of angiogenesis: aortic sprouting in fibrin gels. Angiogenesis was quantitated in this system by a unique application of planar morphometry. Both compounds were found to potently inhibit angiogenesis in this model. To further characterize the activity of these compounds against MMPs, we determined the IC50S of both compounds against representatives of three classes of metalloproteinases: fibroblast collagenase, stromelysin, and gelatinase A. Doxycycline was found to inhibit collagenase, gelatinase A and stromelysin with IC50S of 452 microM, 56 microM and 32 microM, respectively. Minocycline was found to inhibit only stromelysin in the micromolar range with an IC50 of 290 microM. Since these results suggest that these compounds may not have been inhibiting in vitro angiogenesis by an MMP-dependent mechanism, we decided to test the effects of the potent MMP inhibitor BB-94. This compound failed to inhibit aortic sprouting in fibrin gels, thus strongly suggesting that both doxycycline and minocycline act by an MMP-independent mechanism. These results have implications for the mechanism of action of tetracycline analogs, particularly where they are being considered for the treatment of disorders of extracellular matrix degradation including periodontal disease, arthritis, and tumor angiogenesis.

Animals↗
PubMed1998

A novel in vitro system to study extravasated tumor cell-induced angiogenesis.

Angiogenesis, the formation of new blood vessels from preexisting ones, is a fundamental stage in the metastatic pathway. For the primary tumor, this neovascularization provides nutrients and oxygen as well as a route by which metastatic tumor cells gain access to the circulatory system. Among these metastatic tumor cells, there are subgroups of cells that express an angiogenesis-inducing cells phenotype (AICs) as well as others that do not. Tumor cells not expressing the angiogenesis-inducing cells phenotype (non-AICs) invade new tissues and remain as dormant micrometastases unless they accompany AICs. Thus, either alone or with non-AICs, angiogenesis-inducing cells form rapidly growing, clinically detectable metastases. Much of the current research in this area is concentrated on the vascularization of primary tumors, but the regulation of angiogenesis by extravasating or invading tumor cells has not being extensively studied. We have developed a working model, which demonstrates that human metastatic prostate cancer cells (PC-3) appear to induce human vascular endothelial cells (HUVECs) to translocate across a Matrigel-coated 8 mm membrane. The parameters of this model (i.e. pore size, seeding-cell density, seeding times) were established using highly invasive murine melanoma cells (B16F10) seeded on murine microvascular endothelial cells (CD3). We have further modified our model in order to include a host compartment made of collagen gel, in order to mimic the in vivo site of metastases-induced angiogenesis.

Adenocarcinoma↗
PubMed2003

Inhibition of angiogenesis by NSAIDs: molecular mechanisms and clinical implications.

Angiogenesis, the formation of new capillary blood vessels, is a fundamental process essential for reproduction and embryonic development. It is crucial to the healing of tissue injury because it provides essential oxygen and nutrients to the healing site. Angiogenesis is also required for cancer growth and progression since tumor growth requires an increased nutrient and oxygen supply. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used drugs worldwide for treating pain, arthritis, cardiovascular diseases, and more recently for colon cancer prevention. However, NSAIDs produce gastrointestinal ulcers and delay ulcer healing. Recently NSAIDs have been demonstrated to inhibit angiogenesis, but the underlying mechanisms are only beginning to be elucidated. The inhibition of angiogenesis by NSAIDs is a causal factor in the delay of ulcer healing, and it is becoming clear that this is also likely to be one of the mechanisms by which NSAIDs can reduce or prevent cancer growth. Based on the experimental data and the literature, the mechanisms by which NSAIDs inhibit angiogenesis appear to be multifactorial and likely include local changes in angiogenic growth factor expression, alteration in key regulators and mediators of vascular endothelial growth factor (VEGF), increased endothelial cell apoptosis, inhibition of endothelial cell migration, recruitment of inflammatory cells and platelets, and/or thromboxane A2 mediated effects. Some of these mechanisms include: inhibition of mitogen-activated protein (Erk2) kinase activity; suppression of cell cycle proteins; inhibition of early growth response (Egr-1) gene activation; interference with hypoxia inducible factor 1 and VEGF gene activation; increased production of the angiogenesis inhibitor, endostatin; inhibition of endothelial cell proliferation, migration, and spreading; and induction of endothelial apoptosis.

Animals↗
PubMed2002

HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model.

AIMS/HYPOTHESIS: As vascular endothelial growth factor (VEGF) plays a pivotal role in the development of diabetic retinopathy, inhibition of angiogenesis induced by VEGF is crucial to treat diabetic retinopathy. HGF (hepatocyte growth factor)/NK4, containing the N-terminal hairpin domain and the four subsequent kringle domains of HGF, is considered as a specific antagonist for HGF. Our aim was to explore the inhibitory effects of HGF/NK4 on angiogenesis induced by VEGF. METHODS: To analyze the in vivo angiogenesis, we used rabbit corneal micropocket assay. Proliferation and migration of human endothelial cells, expression of ets-1, an essential transcription factor for angiogenesis, and the phosphorylation of extracellular signal-regulated kinase (ERK) was examined with or without HGF/NK4. RESULTS: Using corneal micropocket assay, in vivo administration of HGF/NK4 inhibited angiogenesis induced by VEGF. HGF/NK4 inhibited proliferation and migration of human endothelial cells induced by VEGF in a dose-dependent manner. Interestingly, VEGF-mediated phosphorylation of ERK was significantly attenuated by HGF/NK4. Of importance, HGF/NK4 attenuated the increase in ets-1 protein stimulated by VEGF. Nevertheless, HGF/NK4 did not affect phosphorylation of VEGF receptor-2 [kinase domain region (KDR)/foetal liver kinase (Flk)-1]. Although tyrosine phosphatase inhibitor (Na(3)VO(4)), or okadaic acid, serine-threonin kinase inhibitor, did not prevent the inhibition of ERK phosphorylation by HGF/NK4, co-incubation of HGF/NK4 with VEGF significantly diminished mitogen-activated protein (MAP) ERK kinase (MEK) phosphorylation (p<0.01). CONCLUSIONS/INTERPRETATION: Overall, HGF/NK4 inhibited angiogenesis induced by VEGF through inhibition of phosphorylation of ERK and ets-1 expression in in vitro cultured endothelial cells and in vivo rabbit model.

Animals↗
PubMed2004

Placenta growth factor is not required for exercise-induced angiogenesis.

Angiogenesis is a tightly regulated process, both during development and adult life. Animal models with mutations in the genes coding for placental growth factor (PlGF), a member of vascular endothelial growth factor (VEGF) family, or the tyrosine kinase domain of the PlGF receptor (Flt-1) have revealed differences between normal physiological angiogenesis and pathological angiogenesis associated with conditions such as tumor growth, arthritis and atherosclerosis. In the present paper, we investigated the potential role of PlGF in regulating physiological angiogenesis by analyzing vascular changes in heart and skeletal muscles of wild-type and Plgf-/- mice following prolonged and sustained physical training. Sedentary Plgf-/- mice showed a reduced capillary density in both heart and skeletal muscles as compared to wild-type mice (P < 0.05). However, after a 6-week training period, heart/body weight ratio, citrate synthase activity, vessel density and capillary/myocyte ratio were significantly increased in both wild-type and Plgf-/- mice (all P < 0.05). At the same time intercapillary distance was significantly reduced. Finally, acute exercise was not associated with any change in PlGF protein level in the skeletal muscle. Our results demonstrate that PlGF is not necessary for exercise-training-induced angiogenesis. We thus suggest that the role of PlGF is confined to the selective regulation of angiogenesis only under pathological conditions.

Animals↗
PubMed2005

Angiogenesis during exercise and training.

In this review the factors involved in angiogenesis are discussed in their various roles in initiating angiogenesis and inducing changes in the extracellular matrix to facilitate sprouting angiogenesis which is a major part of the angiogenesis seen in exercise and exercise training. A key role in angiogenesis is played by vascular endothelial growth factor (VEGF). The regulation of blood vessel growth to match the needs of the tissue depends on the control of VEGF production through changes in the stability of its mRNA and in its rate of transcription. The detailed studies describing its characteristics and its upregulation in acute exercise are presented along with a brief overview of the changes in the extracellular matrix that facilitate sprouting angiogenesis that occurs in response to exercise and training. Although the mechanisms involved in the growth and remodeling of arterioles and larger vessels are less detailed some recent studies have provided new insights. These are presented here to show a relationship between capillary development and arteriolar growth or remodeling in exercise training that raises questions to be addressed in future studies.

Coronary Vessels↗
PubMed1993

Radicicol, a microbial cell differentiation modulator, inhibits in vivo angiogenesis.

Angiogenesis plays a significant role in various pathological states, including the progressive growth of solid tumors, rheumatoid arthritis, psoriasis, and diabetic retinopathy, in addition to its crucial role in embryonic development. Recent studies have revealed that an angiogenesis inhibitor is efficacious for these so-called angiogenic diseases. In the previous studies, we found that retinoids and vitamin D3 analogs, which are known to exhibit cell differentiation-modulating activity, effectively inhibit angiogenesis in vivo, thus forming the basis of our working hypothesis that a modulator of cell differentiation is capable of affecting angiogenesis. In this study, to verify this hypothesis further, radicicol (syn. monorden; 5-chloro-6-(7,8-epoxy-10-hydoxy-2-oxo-3,5-undecadienyl)-beta -resorcylic acid mu-lactone), a microbial cell differentiation modulator from a fungus, a strain of Neocosmospora tenuicristata, was examined for its anti-angiogenic activity in a bioassay system involving chorioallantoic membranes of growing chick embryos. The microbial cell differentiation modulator dose dependently inhibited embryonic angiogenesis, the ID50 value being 200 ng/egg. Radicicol also inhibited both the proliferation of and plasminogen activator production by vascular endothelial cells in the nM concentration range in a concentration-dependent manner, suggesting the possible involvement of these inhibitory effects in the anti-angiogenic action of the microbial product. These results indicate that radicicol might be a potential drug for treating different angiogenesis-dependent diseases, such as solid tumors, psoriasis, rheumatoid arthritis, and diabetic retinopathy.

Allantois↗
PubMed2003

STI-571 inhibits in vitro angiogenesis.

Compounds that block angiogenesis are effective in the treatment of certain cancers and other angiogenesis-related diseases. Many of these compounds specifically target the rapidly proliferating and migrating endothelial cell. However, angiogenesis is a multi-faceted process involving heterotypic interactions between various cell types. For example, PDGFBB is an important cytokine secreted by endothelial cells that attracts smooth muscle cells to surround and stabilize a nascent vessel. Therefore, we hypothesized that STI-571, a tyrosine kinase inhibitor with PDGFbeta receptor activity, would inhibit angiogenesis through an anti-migratory effect on smooth muscle cells. We demonstrate that STI-571 completely inhibits in vitro angiogenesis in fibrinogen-embedded mouse aorta. Furthermore, this angiostatic property was due mainly to an anti-migratory and anti-proliferative effect upon smooth muscle cells. These data suggest that STI-571, in addition to its efficacy in the treatment of certain cancers, may also prove to be clinically useful in diseases characterized by unregulated angiogenesis.

Animals↗
PubMed2004

Impaired angiogenesis in SHR is associated with decreased KDR and MT1-MMP expression.

This study examined whether retarded angiogenesis in a hypertension animal model was associated with impaired VEGF signaling. Furthermore, we sought to determine whether this impairment could be overcome by VEGF addition. Using a rat sponge implantation model, we confirmed impaired angiogenesis in spontaneous hypertensive rats (SHRs). Fourteen days after sponge implantation, the level of angiogenesis in SHRs was approximately half of those in age-matched normotensive Wistar-Kyoto or Sprague-Dawley rats. Significantly, expression of kinase-insert domain-containing receptor (KDR) and membrane type 1 matrix metalloproteinase (MT1-MMP) was reduced in SHRs compared to controls. Immunohistological analysis indicated endothelial proliferation was decreased in SHRs. Gene transfer of human VEGF(121) increased KDR and MT1-MMP expression in SHRs. VEGF(121) also up-regulated endothelial proliferation and angiogenesis. Our results indicate down-regulated KDR and MT1-MMP expression is associated with an impaired angiogenesis in SHRs. VEGF gene transfer is effective in ameliorating the impaired angiogenesis in SHRs.

Adenoviridae↗
PubMed2006

Modulation of angiogenesis by tissue inhibitor of metalloproteinase-4.

Despite the importance of MMP activity in the regulation of angiogenesis, relatively little is known about the role of TIMP-4, the most recently discovered endogenous MMP inhibitor, in modulating neovascularization. It has largely been assumed that all TIMPs are capable of inhibiting angiogenesis in vivo. However, it is now widely appreciated that TIMPs-1, -2, and -3 differ significantly in their ability to modulate angiogenic processes in vitro and angiogenesis in vivo. In order to study the effect of TIMP-4 in controlling angiogenesis, we have cloned and expressed TIMP-4 in a Pichia pastoris expression system, purified it to homogeneity, and tested its ability to regulate angiogenesis in vivo and in vitro. Our studies demonstrate that TIMP-4 is an inhibitor of capillary endothelial cell migration, but not of proliferation or of angiogenesis in vivo.

Animals↗
PubMed2005

Regulators of angiogenesis and strategies for their therapeutic manipulation.

Angiogenesis provides a mechanism by which delivery of oxygen and nutrients is adapted to compliment changes in tissue mass or metabolic activity. However, maladaptive angiogenesis is integral to the process of several diseases common in Western countries, including tumor growth, vascular insufficiency, diabetic retinopathy and rheumatoid arthritis. Understanding the process of capillary growth, including the identification and functional analyses of key pro- and anti-angiogenic factors, provides knowledge that can be applied to improve/reverse these pathological states. Initially, angiogenesis research focused predominantly on vascular endothelial growth factor (VEGF) as a main player in the angiogenesis cascade. It is apparent now that participation of multiple angiogenic factors and signal pathways is critical to enable effective growth and maturation of nascent capillaries. The purpose of this review is to focus on recent progress in identifying angiogenesis signaling pathways that show promise as targets for successful induction or inhibition of capillary growth. The strategies applied to achieve these contradictory tasks are discussed within the framework of our existing fundamental knowledge of angiogenesis signaling cascades, with an emphasis on comparing the employment of distinctive tactics in modulation of these pathways. Innovative developments that are presented include: (1) inducing a pleiotropic response via activation or inhibition of angiogenic transcription factors; (2) modulation of nitric oxide tissue concentration; (3) manipulating the kallikrein-kinin system; (4) use of endothelial progenitor cells as a means to either directly contribute to capillary growth or to be used as a vehicle to deliver "suicide genes" to tumor tissue.

Animals↗