http://www.vascularcell.com The most accessed research articles published by Vascular Cell 2011-12-14T00:00:00Z Angiogenesis is disregulated in many diseased states, most notably in cancer. An emerging strategy for the development of therapies targeting tumor-associated angiogenesis is to harness the potential of nanotechnology to improve the pharmacology of chemotherapeutics, including anti-angiogenic agents. Nanoparticles confer several advantages over that of free drugs, including their capability to carry high payloads of therapeutic agents, confer increased half-life and reduced toxicity to the drugs, and provide means for selective targeting of the tumor tissue and vasculature. The plethora of nanovectors available, in addition to the various methods available to combine them with anti-angiogenic drugs, allows researchers to fine-tune the pharmacological profile of the drugs ad infinitum. Use of nanovectors has also opened up novel avenues for non-invasive imaging of tumor angiogenesis. Herein, we review the types of nanovector and therapeutic/diagnostic agent combinations used in targeting tumor angiogenesis. http://www.vascularcell.com/content/3/1/3 Deboshri Banerjee Rania Harfouche Shiladitya Sengupta Vascular Cell 2011, null:3 2011-01-31T00:00:00Z doi:10.1186/2045-824X-3-3 /content/figures/2045-824X-3-3-toc.gif Vascular Cell 2045-824X ${item.volume} 3 2011-01-31T00:00:00Z XML This Commentary emphasizes the fundamental contribution of William Harvey to the discovery of the circulation of the blood and his scientific and experimental approach to this matter. http://www.jangiogenesis.com/content/1/1/3 Domenico Ribatti Vascular Cell 2009, null:3 2009-09-21T00:00:00Z doi:10.1186/2040-2384-1-3 /content/figures/2040-2384-1-3-toc.gif Vascular Cell 2045-824X ${item.volume} 3 2009-09-21T00:00:00Z XML Background: Much of our current understanding of microvascular permeability is based on the findings of classic experimental studies of blood capillary permeability to various-sized lipid-insoluble endogenous and non-endogenous macromolecules. According to the classic small pore theory of microvascular permeability, which was formulated on the basis of the findings of studies on the transcapillary flow rates of various-sized systemically or regionally perfused endogenous macromolecules, transcapillary exchange across the capillary wall takes place through a single population of small pores that are approximately 6 nm in diameter; whereas, according to the dual pore theory of microvascular permeability, which was formulated on the basis of the findings of studies on the accumulation of various-sized systemically or regionally perfused non-endogenous macromolecules in the locoregional tissue lymphatic drainages, transcapillary exchange across the capillary wall also takes place through a separate population of large pores, or capillary leaks, that are between 24 and 60 nm in diameter. The classification of blood capillary types on the basis of differences in the physiologic upper limits of pore size to transvascular flow highlights the differences in the transcapillary exchange routes for the transvascular transport of endogenous and non-endogenous macromolecules across the capillary walls of different blood capillary types. Methods: The findings and published data of studies on capillary wall ultrastructure and capillary microvascular permeability to lipid-insoluble endogenous and non-endogenous molecules from the 1950s to date were reviewed. In this study, the blood capillary types in different tissues and organs were classified on the basis of the physiologic upper limits of pore size to the transvascular flow of lipid-insoluble molecules. Blood capillaries were classified as non-sinusoidal or sinusoidal on the basis of capillary wall basement membrane layer continuity or lack thereof. Non-sinusoidal blood capillaries were further sub-classified as non-fenestrated or fenestrated based on the absence or presence of endothelial cells with fenestrations. The sinusoidal blood capillaries of the liver, myeloid (red) bone marrow, and spleen were sub-classified as reticuloendothelial or non-reticuloendothelial based on the phago-endocytic capacity of the endothelial cells. Results: The physiologic upper limit of pore size for transvascular flow across capillary walls of non-sinusoidal non-fenestrated blood capillaries is less than 1 nm for those with interendothelial cell clefts lined with zona occludens junctions (i.e. brain and spinal cord), and approximately 5 nm for those with clefts lined with macula occludens junctions (i.e. skeletal muscle). The physiologic upper limit of pore size for transvascular flow across the capillary walls of non-sinusoidal fenestrated blood capillaries with diaphragmed fenestrae ranges between 6 and 12 nm (i.e. exocrine and endocrine glands); whereas, the physiologic upper limit of pore size for transvascular flow across the capillary walls of non-sinusoidal fenestrated capillaries with open 'non-diaphragmed' fenestrae is approximately 15 nm (kidney glomerulus). In the case of the sinusoidal reticuloendothelial blood capillaries of myeloid bone marrow, the transvascular transport of non-endogenous macromolecules larger than 5 nm into the bone marrow interstitial space takes place via reticuloendothelial cell-mediated phago-endocytosis and transvascular release, which is the case for systemic bone marrow imaging agents as large as 60 nm in diameter. Conclusions: The physiologic upper limit of pore size in the capillary walls of most non-sinusoidal blood capillaries to the transcapillary passage of lipid-insoluble endogenous and non-endogenous macromolecules ranges between 5 and 12 nm. Therefore, macromolecules larger than the physiologic upper limits of pore size in the non-sinusoidal blood capillary types generally do not accumulate within the respective tissue interstitial spaces and their lymphatic drainages. In the case of reticuloendothelial sinusoidal blood capillaries of myeloid bone marrow, however, non-endogenous macromolecules as large as 60 nm in diameter can distribute into the bone marrow interstitial space via the phago-endocytic route, and then subsequently accumulate in the locoregional lymphatic drainages of tissues following absorption into the lymphatic drainage of periosteal fibrous tissues, which is the lymphatic drainage of myeloid bone marrow. When the ultrastructural basis for transcapillary exchange across the capillary walls of different capillary types is viewed in this light, it becomes evident that the physiologic evidence for the existence of aqueous large pores ranging between 24 and 60 nm in diameter in the capillary walls of blood capillaries, is circumstantial, at best. http://www.jangiogenesis.com/content/2/1/14 Hemant Sarin Vascular Cell 2010, null:14 2010-08-11T00:00:00Z doi:10.1186/2040-2384-2-14 /content/figures/2040-2384-2-14-toc.gif Vascular Cell 2045-824X ${item.volume} 14 2010-08-11T00:00:00Z XML Background: Wnt signaling is activated in many types of cancer and normal physiological processes. Various Wnt-related secreted factors may influence angiogenesis both in the tumor microenvironment and in normal tissues by direct action on endothelial cells. The mechanism of this Wnt action in angiogenesis is not well defined. We hypothesize that endothelial cells are responsive to Wnt signals and that Lef1, a member of the vertebrate-specific Wnt/beta-catenin throughput-inducing transcription factors' sub-family Lef1/Tcf1, mediates this responsiveness and promotes endothelial cell invasion. Methods: A human endothelial cell line, EAhy926 was exposed to Wnt3a or directly transfected with Lef1. Readouts included assessment of nuclear beta-catenin, Wnt throughput with a SuperTOPflash reporter assay, induction of Lef1 transcription, induction of matrix metalloproteinase (MMP)-2 transcription, cell proliferation and cell invasion through a matrix in vitro. The effects on MMP2 were also evaluated in the presence of Lef1 silencing siRNA. Results: Wnt3a increased nuclear beta-catenin and up-regulated Wnt/beta-catenin throughput. Wnt3a increased Lef1 transcription and activity of the Lef1 promoter. Both Wnt3a treatment and Lef1 overexpression induced MMP2 transcription but this effect was completely abrogated in the presence of Lef1 siRNA. Inhibition of Lef1 also reduced basal MMP2 levels suggesting that Lef1 regulates MMP2 expression even in the absence of exogenous Wnt pathway activation. Lef1 slightly increased proliferation of EAhy926 cells and increased invasion by more than two-fold. Conclusions: EAhy926 cells activate canonical Wnt signaling in response to Wnt3a ligand. The Wnt target Lef1 specifically regulates MMP2 expression in these cells and promotes endothelial cell invasion. The EAhy926 cell line provides a convenient alternative to primary human umbilical vein endothelial cells (HUVEC) in the study of angiogenesis and the role of Wnt signaling on endothelial cell function. http://www.vascularcell.com/content/3/1/28 Marina Planutiene Kestutis Planutis Randall Holcombe Vascular Cell 2011, null:28 2011-12-14T00:00:00Z doi:10.1186/2045-824X-3-28 /content/figures/2045-824X-3-28-toc.gif Vascular Cell 2045-824X ${item.volume} 28 2011-12-14T00:00:00Z XML Angiogenesis is a crucial process in tumor pathogenesis as it sustains malignant cells with nutrients and oxygen. It is well known that tumor cells secrete various growth factors, including VEGF, which triggers endothelial cells to form new capillaries. Prevention of expansion of new blood vessel networks results in reduced tumor size and metastasis. Production of VEGF is driven by hypoxia via transcriptional activation of the VEGF gene by HIF-1α.Tumours are now understood to contain different types of cells, and it is the cancer stem cells that retain the ability to drive the tumour's growth. They are called cancer stem cells because, like stem cells present in normal tissues of the body, they can self-renew and differentiate. These cancer stem cells are responsible for the relapse of cancer as they are found to be resistant to conventional modes of cancer therapy like chemotherapy and radiation.In this review, a novel mode of treatment of cancer is proposed, which utilizes the twin nanoparticle to target endothelial cells in the niche of cancer stem cell. The nanoparticle discussed in this review, is a twin nanoparticle of iron coated with gold, which targets VEGF positive cell in the vicinity of cancer stem cell. In the twin nanoparticle, one particle will recognize cancer stem cell, and another conjugated nanoparticle will recognize VEGF positive cells, thereby inhibiting endothelial cells in the proximity of cancer stem cell. This novel strategy will inhibit angiogenesis near cancer stem cell hence new tumour cannot grow and old tumour will be unable to metastasize. http://www.vascularcell.com/content/3/1/26 Rashmi Ambasta Archita Sharma Pravir Kumar Vascular Cell 2011, null:26 2011-11-14T00:00:00Z doi:10.1186/2045-824X-3-26 /content/figures/2045-824X-3-26-toc.gif Vascular Cell 2045-824X ${item.volume} 26 2011-11-14T00:00:00Z XML Angiogenesis is the growth of new blood vessels and is a key process which occurs during both physiological and pathological disease processes. Knowledge of the mechanisms through which this process is initiated and maintained will have a significant impact on the treatment of these diseases. Pathological angiogenesis occurs in major diseases such as cancer, diabetic retinopathies, age-related macular degeneration and atherosclerosis. In other diseases such as stroke and myocardial infarction, insufficient or improper angiogenesis results in tissue loss and ultimately higher morbidity and mortality. http://www.jangiogenesis.com/content/1/1/1 Mark Slevin Yihai Cao Jan Kitajewski Vascular Cell 2009, null:1 2009-09-21T00:00:00Z doi:10.1186/2040-2384-1-1 /content/figures/2040-2384-1-1-toc.gif Vascular Cell 2045-824X ${item.volume} 1 2009-09-21T00:00:00Z XML Background: Endothelial progenitor cells (EPCs) are implicated in a range of pathological conditions, suggesting a natural therapeutic role for EPCs in angiogenesis. However, current angiogenic therapies involving EPC transplantation are inefficient due to rejection of donor EPCs. One solution is to derive an expanded population of EPCs from stem cells in vitro, to be re-introduced as a therapeutic transplant. To demonstrate the therapeutic potential of EPCs we performed in vitro transplantation of EPCs into endothelial cell (EC) tubules using a gel-based tubule formation assay. We also described the production of highly angiogenic EPC-comparable cells from pluripotent embryonic stem cells (ESCs) by direct differentiation using EC-conditioned medium (ECCM). Results: The effect on tubule complexity and longevity varied with transplantation quantity: significant effects were observed when tubules were transplanted with a quantity of EPCs equivalent to 50% of the number of ECs originally seeded on to the assay gel but not with 10% EPC transplantation. Gene expression of the endothelial markers VEGFR2, VE-cadherin and CD31, determined by qPCR, also changed dynamically during transplantation. ECCM-treated ESC-derived progenitor cells exhibited angiogenic potential, demonstrated by in vitro tubule formation, and endothelial-specific gene expression equivalent to natural EPCs. Conclusions: We concluded the effect of EPCs is cumulative and beneficial, relying on upregulation of the angiogenic activity of transplanted cells combined with an increase in proliferative cell number to produce significant effects upon transplantation. Furthermore, EPCs derived from ESCs may be developed for use as a rapidly-expandable alternative for angiogenic transplantation therapy. http://www.vascularcell.com/content/3/1/11 Peter Rae Richard Kelly Stuart Egginton Justin St. John Vascular Cell 2011, null:11 2011-05-11T00:00:00Z doi:10.1186/2045-824X-3-11 /content/figures/2045-824X-3-11-toc.gif Vascular Cell 2045-824X ${item.volume} 11 2011-05-11T00:00:00Z XML Background: Neovascularization (angiogenesis) is a multistep process, controlled by opposing regulatory factors, which plays a crucial role in several ocular diseases. It often results in vitreous hemorrhage, retinal detachment, neovascularization glaucoma and subsequent vision loss. Hypoxia is considered to be one of the key factors to trigger angiogenesis by inducing angiogenic factors (like VEGF) and their receptors mediated by hypoxia inducible factor-1 (HIF-1α) a critical transcriptional factor. Another factor, nuclear factor kappa B (NFκB) also regulates many of the genes required for neovascularization, and can also be activated by hypoxia. The aim of this study was to elucidate the mechanism of interaction between HRPC and HUVEC that modulates a neovascularization response. Methods: Human retinal progenitor cells (HRPC) and human umbilical vein endothelial cells (HUVEC) were cultured/co-cultured under normoxia (control) (20% O2) or hypoxia (1% O2) condition for 24 hr. Controls were monolayer cultures of each cell type maintained alone. We examined the secretion of VEGF by ELISA and influence of conditioned media on blood vessel growth (capillary-like structures) via an angiogenesis assay. Total RNA and protein were extracted from the HRPC and HUVEC (cultured and co-cultured) and analyzed for the expression of VEGF, VEGFR-2, NFκB and HIF-1α by RT-PCR and Western blotting. The cellular localization of NFκB and HIF-1α were studied by immunofluorescence and Western blotting. Results: We found that hypoxia increased exogenous VEGF expression 4-fold in HRPC with a further 2-fold increase when cultured with HUVEC. Additionally, we found that hypoxia induced the expression of the VEGF receptor (VEGFR-2) for HRPC co-cultured with HUVEC. Hypoxia treatment significantly enhanced (8- to 10-fold higher than normoxia controls) VEGF secretion into media whether cells were cultured alone or in a co-culture. Also, hypoxia was found to result in a 3- and 2-fold increase in NFκB and HIF-1α mRNA expression by HRPC and a 4- and 6-fold increase in NFκB and HIF-1α protein by co-cultures, whether non-contacting or contacting.Treatment of HRPC cells with hypoxic HUVEC-CM activated and promoted the translocation of NFκB and HIF-1α to the nuclear compartment. This finding was subsequently confirmed by finding that hypoxic HUVEC-CM resulted in higher expression of NFκB and HIF-1α in the nuclear fraction of HRPC and corresponding decrease in cytoplasmic NFκB and HIF-1α. Lastly, hypoxic conditioned media induced a greater formation of capillary-like structures (angiogenic response) compared to control conditioned media. This effect was attenuated by exogenous anti-human VEGF antibody, suggesting that VEGF was the primary factor in the hypoxic conditioned media responsible for the angiogenic response. Conclusions: These findings suggest that intercellular communications between HRPC and HUVEC lead to the modulation of expression of transcription factors associated with the production of pro-angiogenic factors under hypoxic conditions, which are necessary for an enhanced neovascular response. Our data suggest that the hypoxia treatment results in the up-regulation of both mRNA and protein expression for VEGF and VEGFR-2 through the translocation of NFκB and HIF-1α into the nucleus, and results in enhanced HRPC-induced neovascularization. Hence, a better understanding of the underlying mechanism for these interactions might open perspectives for future retinal neovascularization therapy. http://www.vascularcell.com/content/3/1/27 Ravindra Kumar Sandra Harris-Hooker Ritesh Kumar Gary Sanford Vascular Cell 2011, null:27 2011-11-23T00:00:00Z doi:10.1186/2045-824X-3-27 /content/figures/2045-824X-3-27-toc.gif Vascular Cell 2045-824X ${item.volume} 27 2011-11-23T00:00:00Z XML Tumor angiogenesis is an important target for cancer therapy, with most current therapies designed to block the VEGF signaling pathway. However, clinical resistance to anti-VEGF therapy highlights the need for targeting additional tumor angiogenesis signaling pathways. The endothelial Notch ligand Dll4 (delta-like 4) has recently emerged as a critical regulator of tumor angiogenesis and thus as a promising new therapeutic anti-angiogenesis target. Blockade of Dll4-Notch signaling in tumors results in excessive, non-productive angiogenesis with resultant inhibitory effects on tumor growth, even in some tumors that are resistant to anti-VEGF therapies. As Dll4 inhibitors are entering clinical cancer trials, this review aims to provide current perspectives on the function of the Dll4-Notch signaling axis during tumor angiogenesis and as a target for anti-angiogenic cancer therapy. http://www.vascularcell.com/content/3/1/20 Frank Kuhnert Jessica Kirshner Gavin Thurston Vascular Cell 2011, null:20 2011-09-18T00:00:00Z doi:10.1186/2045-824X-3-20 /content/figures/2045-824X-3-20-toc.gif Vascular Cell 2045-824X ${item.volume} 20 2011-09-18T00:00:00Z XML Background: The negative feedback system is an important physiological regulatory mechanism controlling angiogenesis. Soluble vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1), acts as a potent endogenous soluble inhibitor of VEGF- and placenta growth factor (PlGF)-mediated biological function and can also form dominant-negative complexes with competent full-length VEGF receptors.Methods and resultsSystemic overexpression of VEGF-A in mice resulted in significantly elevated circulating sFlt-1. In addition, stimulation of human umbilical vein endothelial cells (HUVEC) with VEGF-A, induced a five-fold increase in sFlt-1 mRNA, a time-dependent significant increase in the release of sFlt-1 into the culture medium and activation of the flt-1 gene promoter. This response was dependent on VEGF receptor-2 (VEGFR-2) and phosphoinositide-3'-kinase signalling. siRNA-mediated knockdown of sFlt-1 in HUVEC stimulated the activation of endothelial nitric oxide synthase, increased basal and VEGF-induced cell migration and enhanced endothelial tube formation on growth factor reduced Matrigel. In contrast, adenoviral overexpression of sFlt-1 suppressed phosphorylation of VEGFR-2 at tyrosine 951 and ERK-1/-2 MAPK and reduced HUVEC proliferation. Preeclampsia is associated with elevated placental and systemic sFlt-1. Phosphorylation of VEGFR-2 tyrosine 951 was greatly reduced in placenta from preeclamptic patients compared to gestationally-matched normal placenta. Conclusion: These results show that endothelial sFlt-1 expression is regulated by VEGF and acts as an autocrine regulator of endothelial cell function. http://www.vascularcell.com/content/3/1/15 Shakil Ahmad Peter Hewett Bahjat Al-Ani Samir Sissaoui Takeshi Fujisawa Melissa Cudmore Asif Ahmed Vascular Cell 2011, null:15 2011-07-13T00:00:00Z doi:10.1186/2045-824X-3-15 /content/figures/2045-824X-3-15-toc.gif Vascular Cell 2045-824X ${item.volume} 15 2011-07-13T00:00:00Z XML