Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that local angiogenic gene therapy acts, in part, by recruiting endothelial progenitor cells (EPCs) to ischemic tissue. Recent data indicate that patients with the most severe vascular disease may have insufficient or deficient EPCs and the poorest response to angiogenic therapy. Accordingly, we hypothesized that combining human CD34(+) cell implantation with local vascular endothelial growth factor 2 (phVEGF2) gene therapy might overcome these deficiencies. The addition of VEGF2 to EPC cultures resulted in significant and dose-dependent decreases in EPC apoptosis. Phosphorylated Akt (p-Akt) was increased in VEGF2-treated EPCs. In vivo, myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery in 34 immunodeficient rats. The animals were then randomized to one of four treatment groups: cell therapy alone with human CD34(+) cells; VEGF2 gene therapy alone; combination therapy with CD34(+) cells plus phVEGF2; or CD34(-) cells and 50 microg empty plasmid. Four weeks after MI, animals treated with combination therapy showed improved fractional shortening, increased capillary density, and reduced infarct size compared with the other three groups. Combination therapy was also associated with an increased number of circulating EPCs 1 week after MI. Combined subtherapeutic doses of cell and gene therapy result in a significant therapeutic effect compared to monotherapy. This approach may overcome therapeutic failures (e.g. inability of certain patients to mobilize sufficient EPCs) and may also offer safety advantages by allowing lower dosing strategies.
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PMID:Synergistic effect of combined intramyocardial CD34+ cells and VEGF2 gene therapy after MI. 1650 18

The development of blood vessels (angiogenesis) is critical throughout embryogenesis and in some normal postnatal physiological processes. Pathological angiogenesis has a pivotal role in sustaining tumour growth and chronic inflammation. Vascular endothelial growth factor-B (VEGF-B) is a member of the VEGF family of growth factors that regulate blood vessel and lymphatic angiogenesis. VEGF-B is closely related to VEGF-A and placenta growth factor (PlGF), but unlike VEGF-A, which binds to two receptor tyrosine kinases VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR), VEGF-B and PlGF bind to VEGFR-1 and not VEGFR-2. There is growing evidence of a role for VEGF-B in physiological and pathological blood vessel angiogenesis. VEGF-B may provide novel therapeutic strategies for the treatment of vascular disease and be a potential therapeutic target in aberrant vessel formation. To help understand at the molecular level the differential receptor binding profile of the VEGF family of growth factors we have determined the crystal structure of human VEGF-B(10-108) at 2.48 Angstroms resolution. The overall structure is very similar to that of the previously determined cysteine-knot motif growth factors: VEGF-A, PlGF and platelet-derived growth factor-B (PDGF-B). We also present a predicted model for the association of VEGF-B with the second domain of its receptor, VEGFR-1. Based on this interaction and the present structural data of the native protein, we have identified several putative residues that could play an important role in receptor recognition and specificity.
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PMID:Crystal structure of human vascular endothelial growth factor-B: identification of amino acids important for receptor binding. 1661 87

Hypoxia-induced stress plays a central role in retinal vascular disease and cancer. Increased hypoxia-inducible factor-1 alpha (Hif-1 alpha) expression leads to HIF-1 formation and the production of vascular endothelial growth factor (VEGF). Cytokines, including insulin-like growth factor-1 (IGF-1), also stimulate VEGF secretion. In this study, we examined the relationship between IGF-1 signaling, HIF-1 alpha protein turnover and VEGF secretion in the ARPE-19 retinal pigment epithelial cell line. Northern analysis revealed that IGF-1 stimulated Hif-1 alpha message expression, whereas the hypoxia-mimetic CoCl2 did not. CoCl2 treatment increased Hif-1 alpha protein accumulation to a greater extent than IGF-1 treatment. However, IGF-1 stimulated a more significant increase in VEGF secretion. IGF-1-stimulated VEGF promoter activity was phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR (mammalian target of rapamycin)-dependent, whereas VEGF secretion was only partially reduced by inhibition of PI3K/Akt/mTOR and HIF-1 activities. Analysis of VEGF promoter truncation mutants indicated that sensitivity to CoCl2 was hypoxia response element (HRE)-dependent with the region upstream of the HRE conferring IGF-1 sensitivity. In conclusion, IGF-1 regulates VEGF expression and secretion via HIF-1-dependent and -independent pathways.
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PMID:Hypoxia-inducible factor-1-dependent and -independent regulation of insulin-like growth factor-1-stimulated vascular endothelial growth factor secretion. 1668 53

The function of the retina is sensitive to oxygen tension. Any change in the perfusion pressure of the eye affects the retina although the eye is able to autoregulate its hemodynamics. Systemic hypoxemia (lung or heart disease) or a vascular disease in the retina can cause retinal hypoxia. All the hypoxia-dependent events in cells appear to share a common denominator: hypoxia-inducible factor (HIF), which is a heterodimeric transcription factor, a protein. HIF comprises a labile alpha subunit (1-3), which is regulated, and a stable beta subunit, which is constitutively expressed. Both are helix-loop-helix factors and belong to the PAS-domain family of transcription factors. Oxygen plays the key role in stabilizing HIF-1alpha and its function. When the oxygen tension is normal, HIF-1alpha is rapidly oxidized by hydroxylase enzymes, but when cells become hypoxic, HIF-1alpha escapes the degradation and starts to accumulate, triggering the activation of a large number of genes, like vascular endothelial growth factor (VEGF) and erythropoietin. HIF-1alpha has been shown to have, either clinically or experimentally, a mediating or contributing role in several oxygen-dependent retinal diseases such as von Hippel-Lindau, proliferative diabetic retinopathy, retinopathy of prematurity and glaucoma. In retinitis pigmentosa and high-altitude retinopathy, however, the evidence is still indirect. There are three different strategies available for treating retinal diseases, which have all shown promising results: retinal cell transplantation or replacement, gene replacement, and pharmacological intervention. Specifically, recent results show that the HIF pathway can be used as a therapeutic target, although there is still a long way to go from bench to clinic. HIF can be stabilized by inhibiting prolyl hydroxylase or by blocking the VHL:HIF-alpha complex if angiogenesis is the goal, as in retinitis pigmentosa. On the other hand, the downregulation of HIF has a pivotal role if we are to inhibit neovascularization, as in proliferative diabetic retinopathy. To date, several small-molecule inhibitors of HIF have been developed and are entering clinical trials. HIF is a remarkable example of a single transcription factor that can be regarded as a "master switch" regulating all the oxygen-dependent retinal diseases.
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PMID:Oxygen-dependent diseases in the retina: role of hypoxia-inducible factors. 1675 May 26

Embryonic stem (ES) cells are highlighted as promising cell sources for regenerative medicine. Here, we focused on providing the platform that forced ES cells to reproduce the vascular organization process, leading to efficiency and safety evaluation as preclinical testing of biological agents. Murine ES cell-derived embryoid bodies on matrigel, but not collagen or gelatin, could be differentiated into sprouting blood vessels without the addition of growth factors. The expression of endothelial cell marker CD31 and smooth muscle marker alpha-smooth muscle actin was partially colocalized and started to increase 7 days after culture on matrigel, accompanied by the induction of a number of growth factors, such as vascular endothelial growth factor, fibroblast growth factor-2, hepatocyte growth factor, transforming growth factor-beta, and angiopoietin-1. Moreover, notch-related genes, such as Del1 or Del4 (delta-like 1/4) and hey1 or hey2 (hairy/enhancer of split related TRPW motif 1/2), were upregulated in a similar time course. The treatment of neutralizing antibodies against these growth factors failed to inhibit the differentiation into the sprouting blood vessels, whereas arginine-glycine-aspartic peptide, a selective inhibitor for the alphavbeta3-integrins, did inhibit differentiation. An anticancer drug to inhibit angiogenesis, TNP-470, also blocked the vascular formation in this model. ES cells could reproduce the vascular organization process on the biosynthetic scaffolds, such as matrigel, without the addition of growth factors. In the future, a human ES-based tissue model would be an optional tool for the screening of pharmaceutical drugs for vascular disease.
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PMID:Model of vasculogenesis from embryonic stem cells for vascular research and regenerative medicine. 1675 88

Diabetic retinopathy is a micro-angiopathy affecting predominantly small vessels of the retina. Proliferative diabetic retinopathy is characterised by preretinal neovascularisation and fibrosis leading to vitreous heamorrhage and tractional retinal detachment. Chronic hyperglicemia may cause growth factor alterations that are likely to participate in tissue remodeling typical for this late complication. Numerous angiogenic and mitogenic factors have been demonstrated to be present in the eye, including transforming growth factor-beta (TGF-beta), insulin-like growth factors, fibroblast growth factor, tumor necrosis factor and vascular endothelial growth factor. TGF-beta is involved in the control of endothelial cell proliferation, adhesion and deposition of extracellular matrix, thus TGF-beta may play a role in the control of endothelial cell proliferation seen in the disease. The role of TGF-beta in diabetic retinopathy enables better understanding, and thus in the future better intensive antidiabetic therapy in aspect of ophthalmic complications.
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PMID:[The role of transforming growth factor-beta in the pathogenesis of diabetic retinopathy]. 1703 9

15(S)-Hydroxyeicosatetraenoic acid [15(S)-HETE] activated signal transducer and activator of transcription 3 (STAT3) as measured by its tyrosine phosphorylation, translocation from the cytoplasm to the nucleus, DNA binding, and reporter gene activity in human dermal microvascular endothelial cells (HDMVEC). Inhibition of STAT3 activation via adenovirus-mediated expression of its dominant-negative mutant suppressed 15(S)-HETE-induced HDMVEC migration and tube formation in vitro and aortic ring and Matrigel plug angiogenesis in vivo. 15(S)-HETE induced the expression of vascular endothelial growth factor (VEGF) in a time- and STAT3-dependent manner in HDMVEC. In addition, neutralizing anti-VEGF antibodies blocked 15(S)-HETE-induced HDMVEC migration and tube formation in vitro and aortic ring and Matrigel plug angiogenesis in vivo. Together, these results show for the first time that 15(S)-HETE-induced angiogenesis requires STAT3-dependent expression of VEGF. In view of these findings, it is suggested that eicosanoids, particularly 15(S)-HETE, via its capacity to stimulate angiogenesis, may influence the progression of cancer and vascular disease.
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PMID:15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis requires STAT3-dependent expression of VEGF. 1748 46

The burgeoning field of vascular tissue engineering holds promise for the creation of a practical and successful small-diameter arterial bypass graft. Many creative combinations of autologous cells and scaffolds exist along with an equally long list of microenvironmental cues used to create a functional arterial conduit. This review outlines our work using abdominal wall fat as a source of autologous stem cells for vascular tissue engineering, focusing specifically on this stem cell's availability and potency to differentiate into endothelial-like cells. In a series of 49 patients undergoing elective peripheral vascular surgery, an abundant quantity of adult stem cells was harvested from fat obtained by liposuction. The efficacy of the isolation did not appear influenced by advanced age, obesity, renal failure, or vascular disease, although fat from diabetic patients yielded significantly less stem cells. In addition, these adipose-derived stem cells acquired several morphologic and molecular endothelial phenotypes when exposed to growth factors (endothelial cell growth supplement and vascular endothelial growth factor) and physiologic shear stress in vitro. Taken together, these studies suggest that fat appears to be a viable source of autologous stem cells for use in vascular tissue engineering.
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PMID:Tissue engineering applications to vascular bypass graft development: the use of adipose-derived stem cells. 1754 30

Gene therapy is emerging as a potential treatment option in patients suffering from a wide spectrum of cardiovascular diseases including coronary artery disease, peripheral vascular disease, vein graft failure and in-stent restenosis. Thus far preclinical studies have shown promise for a wide variety of genes, in particular the delivery of genes encoding growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) to treat ischaemic vascular disease both peripherally and in coronary artery disease. VEGF as well as other genes such as TIMPs have been used to target the development of neointimal hyperplasia to successfully prevent vein graft failure and in-stent restenosis in animal models. Subsequent phase I trials to examine safety of these therapies have been successful with low levels of serious adverse effects, and albeit in the absence of a placebo group some suggestion of efficacy. Phase 2 studies, which have incorporated a placebo group, have not confirmed this early promise of efficacy. In the next generation of clinical gene therapy trials for cardiovascular disease, many parameters will need to be adjusted in the search for an effective therapy, including the identification of a suitable vector, appropriate gene or genes and an effective vector delivery system for a specific disease target. Here we review the current status of cardiovascular gene therapy and the potential for this approach to become a viable treatment option.
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PMID:Cardiovascular gene therapy: current status and therapeutic potential. 1755 39

Independent of the association of obesity with dyslipidemia, hypertension, and increased propensity for diabetes, fatness per se is increasingly recognized as a cardiovascular offender. That adipose tissue releases a wide range of adipokines, growth factors, enzymes, and enzyme substrates linked to vascular injury provides a plausible explanation for the role of fat in vascular disease: tumor necrosis factor-alpha, leptin, resistin, interleukin-1, -6, -8, and -18, serum amyloid A, monocyte chemoattractant protein I, macrophage inhibitory factor, aortic carboxypeptidase, hepa-rin-binding epidermal growth factor-like growth factor, vascular endothelial growth factor, transforming growth factor beta, angiotensinogen, cathepsin S, estradiol, cortisol, mineralocorticoid releasing factor, and calcitonin peptides are probable fat-derived prothrombotic, proinflammatory, and proatherosclerotic agents acting in a paracrine and/or endocrine manner. Other adipocyte products such as adiponectin, transforming growth factor beta, and interleukin-10 exert some antiatherogenic effects. The following is a short overview of how adipose tissue products affect the vasculature.
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PMID:Fat cell-derived modulators of vascular cell pathophysiology: the list keeps growing. 1767 16


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