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Results for “Neovascularization, Pathologic”

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PubMed2002

Constitutive and inducible nitric oxide synthase: role in angiogenesis.

Since the initial report of nitric oxide (NO) activity, enormous progress has been made over the last two decades in the field of NO research. Whereas most physiological responses triggered by moderate concentrations of NO are mediated by soluble guanylate cyclase activation and the subsequent production of cyclic GMP as the major signaling messenger, recent studies have provided evidence of alternative signaling pathways triggered by high concentrations of NO. These signals operate in part through redox-sensitive regulation of transcription factors, gene expression, transcription, cellular activation, proliferation, and cell death. Numerous results converge to indicate a role for NO in physiological and pathological angiogenesis. Experimental data indicate that NO synthase, depending on the isoforms, the timing, and the degree of activation, may display contradictory effects, expressed during both physiological and pathological angiogenesis. The dual personality of NO will be reviewed in the context of the angiogenesis process.

Animals↗

PubMed2006

An intracrine view of angiogenesis.

Angiogenesis, the generation of new blood vessels from pre-existing vessels, is an integral component of wound healing, responses to inflammation and other physiologic processes. It is also an essential part of tumor growth; in the absence of new vessel formation, tumors cannot expand beyond a small volume. Although much is known about angiogenesis and its regulation, there is no overall theory that describes or explains this process. It is here suggested that the intracrine hypothesis, which ascribes to certain extracellular signaling peptides (whether hormones, growth factors, DNA-binding proteins or enzymes) a role in both intracellular biology and extracellular signaling, can contribute to a more general understanding of angiogenesis. Intracrine factors participate in angiogenesis in the following ways: (1) they can act within the cells that synthesized them (type I intracrine action), (2) they can be secreted and then taken up by their cell of synthesis to act intracellularly (type II intracrine action ), or (3) they can be secreted and internalized by a distant target cell (type III intracrine action). The parallels between the intracrine growth factor mechanisms cancer cells employ in stimulating their own growth and the mechanisms operative in endothelial cell proliferation during angiogenesis ("intracrine reciprocity") are discussed. Collectively, these explorations lead to testable hypotheses regarding the regulation of normal and pathological angiogenesis, and point to similarities between tumor-induced angiogenesis and tissue differentiation.

Animals↗

PubMed2000

Inhibition of vascular endothelial growth factor (VEGF) as a novel approach for cancer therapy.

Of the numerous growth factors and cytokines that have been shown to have angiogenic effects, vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), appears to be a key factor in pathological situations which involve neovascularization as well as enhanced vascular permeability. Our aim was to design a low molecular weight synthetic molecule that potently and selectively blocks the VEGF/VEGF receptor system after oral administration, suitable for the chronic therapy of VEGF-dependent pathological neovascularization. PTK787/ZK 222584 is a potent inhibitor of VEGF receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, like the PDGFR-beta tyrosine kinase, c-Kit and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families such as EGFR, FGFR-1, c-Met and Tie-2 or intracellular kinases like c-Src, c-Abl, PKC-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of KDR, and endothelial cell proliferation, migration and survival in the nanomolar range in cell based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or anti-proliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF- and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown subcutaneously in nude mice, as well as a murine renal carcinoma and its metastases in syngeneic, orthotopic models. Histological examination of tumors reveals inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 also significantly inhibits ascites formation induced by a human ovarian carcinoma grown in the peritoneum of nude mice as well as pleural effusion induced by a human lung adenocarcinoma in nude mice. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent, or impair hematopoetic recovery following concomitant cytotoxic anti-cancer agent challenge. These studies indicate that compounds that inhibit the effects of VEGF, such as PTK787/ZK 222584, have the potential to provide a novel, effective and well-tolerated therapy for the treatment of solid tumors. These agents may also provide a new therapeutic approach for the treatment of other diseases where angiogenesis plays an important role.

Angiogenesis Inhibitors↗

PubMed1997

[Receptors for factors of the VEGF (Vascular Endothelial Growth Family)].

Growth factors of the VEGF (vascular endothelial growth factor) family comprises 4 well characterized members that play a crucial role in the biology of blood vessels. They interact with 3 high affinity tyrosine kinase receptors (FLT1/VEGFR1, FLK1/KDR/VEGFR2, FLT4/VEGFR3). VEGF/VEGFR interactions have essential functions in blood vessel formation during development, specific phases of adult life, and in some pathological processes with neo-vascularization such as tumor growth.

Adult↗

PubMed1996

In vivo experimental evidence that the nitric oxide pathway is involved in the X-ray-induced antiangiogenicity.

We have investigated both the effects of X-rays on angiogenesis and the possible role of nitric oxide (NO) on the observed antiangiogenic effect of X-rays, using as an in vivo model the chick embryo chorioallantoic membrane (CAM). These effects were assessed both morphologically and biochemically, by measuring vascular density and collagenous protein biosynthesis, respectively, on days 9 and 14 of the chick embryo development. Vascular density and cytotoxicity of the CAM were also evaluated histologically. We have shown that X-rays have an antiangiogenic effect on the system used and that the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) promoted angiogenesis of the non-irradiated CAM and reversed the antiangiogenic effect of irradiation. D-NAME, which is an inactive enantiomer of L-NAME, showed no such effects. L-Arginine, which is the substrate for NO synthase, had a modest antiangiogenic effect on the non-irradiated CAM, no effect on the irradiated CAM and abolished the angiogenic effect of L-NAME on these CAM preparations. These results suggest that NO is involved in the antiangiogenic mechanism of X-rays and that pharmacological manipulation of NO firstly, may offer a better understanding of these mechanisms and, secondly, may also prove to be an alternative therapeutic approach for treating pathological conditions involving angiogenesis.

Animals↗

PubMed2000

The role of homeobox genes in vascular remodeling and angiogenesis.

Homeodomain-containing transcription factors are critical in the regulation of cell proliferation, differentiation, and migration, and they play an important role in organogenesis and pattern formation during embryogenesis. There is evidence that some of them are oncogenes or tumor suppressors. The cardiovascular system undergoes extensive remodeling during embryogenesis and disease states such as atherosclerosis and tumor-induced angiogenesis, and homeobox genes may play an important role in regulating these processes. Recently, homeobox genes have been detected in both vascular smooth muscle and endothelial cells, and they are implicated in pathological processes such as arterial restenosis after balloon angioplasty and tumor-induced angiogenesis. The cellular function of some of these genes is beginning to be elucidated. Therefore, we briefly review what is currently known about the involvement of homeobox transcription factors in both physiological and pathological vascular remodeling and angiogenesis.

Cardiovascular System↗

PubMed1999

Role of vascular endothelial growth factor in the regulation of angiogenesis.

Compelling evidence indicates that vascular endothelial growth factor (VEGF) is a fundamental regulator of normal and abnormal angiogenesis. The loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF plays also a critical role in kidney development, and its inactivation during early postnatal life results in the suppression of glomerular development and kidney failure. Recent evidence indicates that VEGF is also essential for angiogenesis in the female reproductive tract and for morphogenesis of the epiphyseal growth plate and endochondral bone formation. Substantial experimental evidence also implicates VEGF in pathological angiogenesis. Anti-VEGF monoclonal antibodies or other VEGF inhibitors block the growth of several human tumor cell lines in nude mice. Furthermore, the concentrations of VEGF are elevated in the aqueous and vitreous humors of patients with proliferative retinopathies such as the diabetic retinopathy. In addition, VEGF-induced angiogenesis results in a therapeutic benefit in several animal models of myocardial or limb ischemia. Currently, both therapeutic angiogenesis using recombinant VEGF or VEGF gene transfer and inhibition of VEGF-mediated pathological angiogenesis are being pursued clinically.

Animals↗

PubMed1997

Angiogenesis in embryos and ischemic diseases.

Angiogenic growth factors and their endothelial receptors are thought to function as major regulators of blood vessel formation. Vascular endothelial growth factor (VEGF) and its receptors, Flt-1 (VEGFR-1) and Flk-1 (VEGFR-2), as well as Angiopoietin-1 and its receptor, Tie-2, represent key signal transduction systems involved in the regulation of embryonic vascular development. The expression of these molecules correlates with phases of blood vessel formation during embryogenesis. Inactivation of any of the genes encoding these molecules in mouse embryos results in defective vascular development and embryonic lethality around mid-gestation. In addition, the VEGF signal transduction system has been implicated in the regulation of pathological blood vessel growth during certain angiogenesis-dependent diseases that are often associated with tissue ischemia, such as proliferative retinopathy or solid tumor growth. This hypothesis is substantiated by experiments, in which the inhibition of VEGF signal transduction resulted in the the inhibition of neovascularization in these diseases. Thus, the VEGF signal transduction system represents a useful target for an anti-angiogenic therapy.

Animals↗

PubMed1999

Molecular and biological properties of vascular endothelial growth factor.

Vascular endothelial growth factor (VEGF) is a fundamental regulator of normal and abnormal angiogenesis. Recent evidence indicates that VEGF is essential for embryonic vasculogenesis and angiogenesis. Furthermore, VEGF is required for the cyclical blood vessel proliferation in the female reproductive tract and for longitudinal bone growth and endochondral bone formation. Substantial experimental evidence also implicates VEGF in pathological angiogenesis. Anti-VEGF monoclonal antibodies or other VEGF inhibitors block the growth of many tumor cell lines in nude mice. Furthermore, the concentrations of VEGF are elevated in the aqueous and vitreous humors of patients with proliferative retinopathies such as the diabetic retinopathy. In addition, VEGF-induced angiogenesis results in a therapeutic benefit in several animal models of myocardial or limb ischemia. Currently, both therapeutic angiogenesis using recombinant VEGF or VEGF gene transfer and inhibition of VEGF-mediated pathological angiogenesis are being pursued.

Animals↗

PubMed2002

Vascularisation of tissue-engineered grafts: the regulation of angiogenesis in reconstructive surgery and in disease states.

Angiogenesis (the formation of new blood vessels) is essential for the growth of new tissue, tissue repair and wound healing. Tissue engineering, the construction of new tissue and organs for reparative purposes, relies on angiogenesis for the vascularisation of these new grafts. In tissue engineering, the emphasis to date has been on vascularisation of newly constructed tissue grafts by an extrinsic blood supply, and relatively little attention has been given to the possibility of building these grafts around an intrinsic blood supply. However, there are many disease processes, notably tumour growth, where excess angiogenesis can be a major problem. The purposes of this review are, first, to examine various methods of vascularising tissue-engineered grafts, and, second, to compare the role of angiogenesis in tissue engineering, where stimulation of angiogenesis is paramount, with pathological states, such as tumour growth, where angiogenesis needs to be inhibited.

Artificial Organs↗

PubMed2000

Vascular-specific growth factors and blood vessel formation.

A recent explosion in newly discovered vascular growth factors has coincided with exploitation of powerful new genetic approaches for studying vascular development. An emerging rule is that all of these factors must be used in perfect harmony to form functional vessels. These new findings also demand re-evaluation of therapeutic efforts aimed at regulating blood vessel growth in ischaemia, cancer and other pathological settings.

Angiopoietin-2↗

PubMed2005

In silico analysis of angiogenesis associated gene expression identifies angiogenic stage related profiles.

In vitro models have been extensively used to map gene expression in ECs but few studies have used cells from in vivo sources directly. Here, we compare different gene expression surveys on both cultured and fresh tissue derived ECs, and it emerges that gene expression profiles can be paralleled with the angiogenic stage of the cells. ECs stimulated with different growth factors in monolayer cultures exhibit gene expression profiles indicative of an active proliferative state, whereas gene expression in tube forming cells in vitro involves genes implicated in cell adhesion processes. Genes overexpressed in tumor ECs are biased towards extracellular matrix remodeling, a late event in angiogenesis. The elucidation of gene expression profiles under these different conditions will contribute to a better understanding of the molecular mechanisms during angiogenesis in both pathological and physiological circumstances and will have implications for the development of angiogenesis interfering treatment strategies.

Animals↗

PubMed2000

Angiogenesis of the ovary.

We present current data pertaining to angiogenesis of the ovary throughout the follicular and luteal phases of the ovarian cycle, in various ovarian pathologic conditions and in benign and neoplastic diseases. MEDLINE, Current Contents, and Index Medicus were searched for studies published between January 1966 and October 1998. All studies that incorporated human and animal models of angiogenesis of the normal ovarian physiologic state and pathologic conditions including both benign and neoplastic ovarian diseases were reviewed. Current literature supports that angiogenesis is an important component of both follicular and luteal phases of the ovarian cycle that correlates well with maturation of secretory endometrium. Angiogenesis also participates in various pathologic processes of the ovary, including follicular cyst formation, polycystic ovary, ovarian hyperstimulation syndrome, and both benign and malignant ovarian neoplasms. In the future a knowledge of specific angiogenic patterns of various pathologic processes may assist in the application of antiangiogenic medications in targeted therapy of benign and neoplastic diseases of the ovary.

Female↗

PubMed2005

Angiogenesis: update 2005.

Angiogenesis has critical roles in normal vascular development and in important pathologies including cancer, wound healing and inflammation. This brief article will review the angiogenic response induced by the vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) family of proteins and particularly VEGF-A, thought to be the single most important angiogenic factor. It will also review the steps and mechanisms by which VEGF-A induces the formation of new blood vessels and will provide an initial classification of the abnormal blood vessels that form in pathological angiogenesis. Finally, it will touch on the exciting relationships that are emerging between angiogenesis and the hemostatic and nervous systems.

Animals↗

PubMed2005

[VEGF as an angiogenic, neurotrophic, and neuroprotective factor].

Vascular endothelial growth factor (VEGF, occurring in several isoforms: VEGF-A, -B, -C, -D) is a well-known endothelial cell mitogen and vascular growth and permeability factor. Recent work done over the last few years has elucidated the important role of VEGF, which participates in the regulation of normal (physiological or therapeutic) and pathological angiogenesis (VEGF-A, VEGF-B) and lymphangiogenesis (VEGF-C, VEGF-D). VEGF has also been implicated in practically every stage of angiogenesis, yet its role in the initiation of new blood vessel creation appears to be the most important. In addition to its role as a key angiogenic factor, VEGF also possesses neurotrophic and neuroprotective activity both in the peripheral and in the central nervous system, exerting a direct action on neurons, Schwann cells, astrocytes, neural stem cells, and microglia. VEGF interacts with three subtypes of VEGF receptors occurring on the cellular membrane known as VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/KDR), and VEGFR-3 (Flt-4). All these receptor types possess an internal tyrosin kinase domain. Interaction of VEGF with particular subtypes of receptors activates a circuit of signaling pathways, e.g. PI3K/Akt, Ras/Raf-MEK/Erk, eNOS/NO, and IP3/Ca2+. These participate in the generation of specific biological responses connected with proliferation, migration, increasing vascular permeability, or promoting endothelial cell survival. Recent findings from experiments performed on animals with experimentally evoked focal cerebral ischemia suggest that the neuroprotective activity of VEGF runs in parallel with its ability to promote neurogenesis and angiogenesis and that these effects may operate independently through multiple mechanisms. The above-mentioned three major features characterizing the neurobiological activity of VEGF, i.e. neuroprotection, neurogenesis, and angiogenesis, together with their possible functional link(s), provide the rationale for considering VEGF-based therapy as a promising future avenue for a more effective treatment of at least some neurodegenerative disorders and stroke. Moreover, the possibility of using neutralizing factors of VEGF or VEGF receptor antagonists may reveal a way of preventing many dangerous pathologies, including post-ischemic disturbances in cardiac and neurological disorders, tumor growth, or hypervascularization in avascular structures of the eye.

Animals↗

PubMed2005

Selective suppression of pathologic, but not physiologic, retinal neovascularization by blocking the angiotensin II type 1 receptor.

PURPOSE: To investigate the anti-inflammatory and anti-angiogenic effects of telmisartan, an angiotensin II type 1 receptor (AT1-R) antagonist, on ischemia-induced retinal neovascularization. METHODS: C57BL/6 neonatal mice were reared in an 80% concentration of oxygen from postnatal day (P)7 to P12, followed by room-air breathing until P17, to induce ischemia-initiated retinal neovascularization (i.e., a murine model of ischemic retinopathy). Tissue localization of AT1-R was examined by immunohistochemistry for murine retinal wholemounts and human fibrovascular tissues excised at vitrectomy for proliferative diabetic retinopathy. Animals received intraperitoneal injection of telmisartan or vehicle. A concanavalin A lectin perfusion-labeling technique was used to evaluate the areas of physiological and pathologic retinal new vessels and the number of leukocytes adhering to the vasculature. Retinal mRNA and protein levels of intercellular adhesion molecule (ICAM)-1, vascular endothelial growth factor receptor (VEGFR)-1, and VEGFR-2 were examined by RT-PCR and ELISA. RESULTS: Vessels in human fibrovascular tissues and the murine retinas were positive for AT1-R. Pathologic (P < 0.01), but not physiologic (P > 0.05), retinal neovascularization was significantly suppressed in telmisartan-treated mice compared with vehicle-treated animals. The number of adherent leukocytes (P < 0.01) was also significantly reduced, together with retinal ICAM-1 levels (P < 0.01) in the telmisartan-treated group compared with the control group. No significant difference was detected in retinal VEGFR-2 levels between the two groups, whereas retinal VEGFR-1 levels in the telmisartan-treated group were significantly (P < 0.05) lower than in the vehicle-treated group. CONCLUSIONS: The present findings suggest that the AT1-R signaling blockade leads to the selective suppression of pathologic, but not physiological, retinal neovascularization through the inhibition of the inflammatory processes related to pathologic neovascularization.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2006

Regulation of angiogenesis by hypoxia-inducible factor 1.

Hypoxia is an imbalance between oxygen supply and demand that occurs in cancer and in ischemic cardiovascular disease. Hypoxia-inducible factor 1 (HIF-1) was originally identified as the transcription factor that mediates hypoxia-induced erythropoietin expression. More recently, the delineation of molecular mechanisms of angiogenesis has revealed a critical role for HIF-1 in the regulation of angiogenic growth factors. In this review, we discuss the role of HIF-1 in developmental, adaptive and pathological angiogenesis. In addition, potential therapeutic interventions involving modulation of HIF-1 activity in ischemic cardiovascular disease and cancer will be discussed.

Animals↗

PubMed1999

VEGFs, receptors and angiogenesis.

Angiogenesis, the formation of new blood vessels from pre--existing ones, is central for both normal development and homeostasis as well as in certain pathological conditions. The vascular endothelial growth factors (VEGFs) and their receptors are prime regulators of both physiological and pathological angiogenesis. The different VEGFs have overlapping but specific roles in controlling the growth of new blood vessels. The VEGF receptors transduce signals mediating endothelial cell proliferation, migration, organization into functional vessels and remodeling of the vessel network. In recent years, rapid progress has been made in understanding the receptor-ligand interactions that orchestrate the neovascularization process.

Animals↗