N Ferrara

..Therapeutic angiogenesis (promoting new vessel growth to treat ischaemic disorders) is an exciting frontier of cardiovascular medicine, but further understanding of the mechanisms of vascular morphogenesis is needed first...

..Thus, G-CSF may promote tumor angiogenesis through a Bv8-dependent pathway that bypasses VEGF and renders tumors refractory to anti-VEGF therapy...

..Substantial evidence also implicates VEGF as an angiogenic mediator in tumors and intraocular neovascular syndromes, and numerous clinical trials are presently testing the hypothesis that inhibition of VEGF may have therapeutic value...

..Currently, both therapeutic angiogenesis using recombinant VEGF or VEGF gene transfer and inhibition of VEGF-mediated pathological angiogenesis are being pursued clinically...

..Currently, both therapeutic angiogenesis using recombinant VEGF or VEGF gene transfer and inhibition of VEGF-mediated pathological angiogenesis are being pursued...

..Bv8 expression is mainly restricted to the testis. The identification of these tissue-selective angiogenic factors raises the possibility that other secreted molecules with selectivity for the endothelium of other organs exist...

..These concepts are being tested now in clinical trials...

..VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration...

..Substantial evidence also implicates VEGF in tumors and intraocular neovascular syndromes. Currently, several clinical trials are ongoing to test the hypothesis that the inhibition of VEGF activity may be beneficial for these conditions...

..How did this field begin, and how have we arrived at our present understanding of the role of VEGF in tumour progression...

..Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration...

..Of these, bevacizumab, a humanized monoclonal antibody directed at VEGF, is the most advanced in clinical development and has shown promising results in clinical trials...

..Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration...

..This review describes recent findings on the role of myeloid cells in refractoriness or/and acquired resistance to such therapies...

..This retrospective article examines the early studies and also emphasizes the subsequent progress in our understanding of these processes in health and disease...

..This article examines the molecular and biological characteristics of VEGF and also discusses preclinical and clinical studies with VEGF inhibitors and the lessons learned from these studies...

..The present review examines the role of tumor- as well as stromal cell-derived pathways involved in tumor growth and in refractoriness to anti-VEGF therapies...

..Substantial evidence also implicates VEGF in tumors and intraocular neovascular syndromes. Currently, several clinical trials are ongoing to test the hypothesis that inhibition of VEGF activity may be beneficial for these conditions...

..This brief review provides a historic account of the challenges associated with the discovery of VEGF and the early steps in elucidating the role of this molecule in the regulation of angiogenesis...

..S. Food and Drug Administration for the treatment of cancer and the neovascular form of age-related macular degeneration. This review summarizes the basic biology of VEGF-A and illustrates the clinical progress in targeting this molecule...

..Among these, ranibizumab is a high affinity recombinant Fab that neutralizes all isoforms of VEGF-A. The article briefly reviews the biology of VEGF and then focuses on the path that led to clinical development of ranibizumab...

..The present findings indicate that removal of the carboxyl-terminal domain, whether it is due to alternative splicing of mRNA or to proteolysis, is associated with a significant loss in bioactivity...

..Thus, VEGF is essential for growth and survival in early postnatal life. However, in the fully developed animal, VEGF is likely to be involved primarily in active angiogenesis processes such as corpus luteum development...

..EG-VEGF is an example of a class of highly specific mitogens that act to regulate proliferation and differentiation of the vascular endothelium in a tissue-specific manner...

..Purified PIGF isoforms had little or no direct mitogenic or permeability-enhancing activity. However, they were able to significantly potentiate the action of low concentrations of VEGF in vitro and, more strikingly, in vivo...

..We also demonstrate that KDR, but not Flt-1, stimulation is responsible for the induction of vascular permeability by VEGF...

..Furthermore, this mutational analysis implicates KDR, but not FLT-1, in VEGF induction of endothelial cell proliferation...

..Furthermore, they have implications for the control of fertility and the treatment of ovarian disorders characterized by hypervascularity and hyperplasia...

..The differences in pharmacokinetics and tissue distribution that are noted between the full-length and Fab antibodies in this study identify potential therapeutic approaches that may be exploited in specific disease conditions...

..In addition, some residues in domain 3 contribute to binding (Asp231) or provide for additional discrimination between ligands (Arg280-Asp283)...

..Angiogenesis and blood-island formation were impaired, resulting in several developmental anomalies. Furthermore, VEGF-null embryonic stem cells exhibit a dramatically reduced ability to form tumours in nude mice...

..These results define a novel functional domain that serves to repress Flt-1 activity in endothelial cells...

..Inhibition of apoptosis may represent a major aspect of the regulatory activity of VEGF on the vascular endothelium...

..A prolonged high-dose dobutamine challenge was monitored by MRI. A maximal response was sustained for 90 minutes, suggesting that it did not depend on endogenous glycogen stores...

..These results demonstrate that antagonism of VEGF reduces ischemia/reperfusion-related brain edema and injury, implicating VEGF in the pathogenesis of stroke and related disorders...

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..However, this LPA response is not evident in normal ovarian surface epithelial cells. Our data suggest that Edg4, but not Edg2, plays a role in LPA stimulation of ovarian tumor growth...

..Human 293 cells transfected with an expression vector containing a bovine or human VEGF cDNA insert secrete an endothelial cell mitogen that behaves like native VEGF...

..These findings indicate that, unlike the KDR/Flk-1 gene, the Flt-1 receptor gene is directly up-regulated by hypoxia via a hypoxia-inducible enhancer element located at positions -976 to -937 of the Flt-1 promoter...

..We suggest that combination therapy using HGF and VEGF co-administration may provide a more effective strategy to achieve therapeutic angiogenesis...

..Thus, alternative splicing of VEGF RNA can produce four polypeptides with strikingly different secretion patterns, which suggests multiple physiological roles for this family of proteins...

..Thus, in addition to its direct, growth stimulatory effect on transformed cells, IGF-I induces the expression of VEGF which can promote the progression of cancer by regulating the development of new blood vessels...

..Microsequencing reveals a unique N-terminal amino acid sequence. On the basis of its apparent target cell selectivity, we propose to name this factor vascular endothelial growth factor (VEGF)...

..The fundamental importance of chondrocytes in the growth, development and repair of the skeleton has led to intense investigation of the mechanisms that regulate chondrocyte maturation and apoptosis...

..We also discuss current knowledge of physiological angiogenic processes as well as their disruptions in pathological processes, particularly tumorigenesis...

..Thus, hypoxia-inducible factor-1alpha-independent expression of VEGF is essential for choroid development...

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..Thus, the functional contribution of stromal VEGF varies greatly among tumors, and systemic blockade of both tumor and stroma-derived VEGF is sufficient for inhibiting the growth of tumor xenografts...

..The best-studied and most advanced approach to VEGF inhibition is the humanized monoclonal antibody bevacizumab (Avastin), which is the only anti-angiogenic agent approved for treatment of cancer...

..We propose that therapies targeting this stromal cell type may be effective in treating certain types of solid tumors...

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..This brief review focuses on the progress in targeting one of the major regulators of angiogenesis, VEGF-A, and also discusses potential cellular and molecular mechanisms underlying resistance to antiangiogenic treatments...

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..These observations provide evidence that glomerular injury in patients who are treated with bevacizumab is probably due to direct targeting of VEGF by antiangiogenic therapy...

..The purpose of this study was to evaluate different methods of detecting and quantifying experimentally induced choroidal neovascularization (CNV) and vascular changes induced on CNV by an anti-VEGF-A monoclonal antibody...

..In summary, our studies verify a role for Bv8 in the mobilization and recruitment of myeloid cells and in the induction of tumor angiogenesis in the early stages of neoplastic progression...

..However, a recent study reported that bevacizumab is a potent inhibitor of hemangiogenesis and lymphangiogenesis in murine models. The authors sought to reassess the interaction between bevacizumab and mVEGF-A...

..These results reveal a cell-autonomous VEGF signaling pathway that holds significance for vascular homeostasis but is dispensable for the angiogenic cascade...

..These findings indicate that, in our models, refractoriness to anti-VEGF treatment is determined by the ability of tumors to prime and recruit CD11b+Gr1+ cells...

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..Therefore, VEGF-A inhibition may be a previously uncharacterized strategy for the prevention of the angiogenic switch and growth in intestinal adenomas...

..However, higher-affinity antibodies were more likely to result in glomerulosclerosis during long-term treatment...

..Thus, Bv8 modulates mobilization of CD11b+Gr1+ cells from the bone marrow during tumour development and also promotes angiogenesis locally...

..The absence of compensatory VEGFR-1 signaling by VEGF-B and PlGF may have important implications for the development of anticancer strategies targeting the VEGF ligand/receptor system...

..This role for HIF-1alpha demonstrates its direct regulation of survival and function in the inflammatory microenvironment...

..The testis exhibits relatively high turnover of endothelial cells. Therefore, Bv8 and EG-VEGF, along with other factors such as VEGF-A, may maintain the integrity and also regulate proliferation of the blood vessels in the testis...

..Thus, VEGFR-1 agonists may have therapeutic potential for preservation of organ function in certain liver disorders...

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..Clinical efficacy of antiangiogenic therapy with bevacizumab is being evaluated in several phase 3 trials in various types of cancer, as well as in patients with age-related macular degeneration...

..Thus, combination therapy with inhibitors of VEGF plus paclitaxel may be an effective way to markedly reduce tumor growth and ascites in ovarian carcinoma...

..Endocrine gland-derived VEGF represents the first example of a tissue-specific angiogenic factor, likely to be followed by others...

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..Not only ligands selective for VEGF and VEGFR-2 but also VEGFR-1 agonists rescued survival and repopulation of VEGF-deficient HSCs, revealing a function for VEGFR-1 signalling during haematopoiesis...

..Thus, VEGF-A is crucial for angiogenesis in a prototypical model of carcinogenesis, whose loss is not readily compensated...

..Taken together, our data demonstrate that ANGPTL3 is the first member of the angiopoietin-like family of secreted factors binding to integrin alpha(v)beta(3) and suggest a possible role in the regulation of angiogenesis...

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..Taken together, these findings point to the central role of VEGFR-2 in the angiogenic signaling pathways induced by VEGF-C(deltaNdeltaC) and VEGF-A...

..We propose that mouse EG-VEGF, like human EG-VEGF, plays a role in regulating the phenotype and growth properties of endothelial cells within distinct capillary beds...

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..Finally, safety pharmacology studies with bevacizumab in cynomolgus monkeys showed that this agent is generally well tolerated with no unexpected adverse events...

..Bv8 potentially modulates growth, survival, and function of cells of the innate and adaptive immune systems, possibly through autocrine or paracrine signaling mechanisms...

..We thus show that a HIF-1alpha-driven, VEGF-mediated autocrine loop in EC is an essential component of solid tumor angiogenesis...

..CONCLUSIONS: Our findings indicate that adventitial angiogenesis stimulates intimal thickening but does not initiate it...

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..MRI assays of microvascular status as performed here may be useful to clinically monitor responses to anti-angiogenesis drugs and to optimize the choice and timing of cytotoxic drug administration...

..Thus, PDGFR alpha signaling is required for the recruitment of VEGF-producing stromal fibroblasts for tumor angiogenesis and growth. Our findings highlight a novel aspect of PDGFR alpha signaling in tumorigenesis...

..Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy...

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..The potential advantage of tissue-specific angiogenic therapeutics may be the reduction of systemic side effects. Additionally, these peptides or their receptors may be attractive targets for inhibition in several disorders...

..These results demonstrate that HIF-1alpha has differential roles in tumor progression, which are greatly dependent on the extant microenvironment of the tumor...

..05) increase in vasa vasorum ingrowth and neointima formation. We conclude that VEGF plays an important role in the formation of neointimal mounds and vasa vasorum ingrowth during permanent ductus closure...

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