D W Losordo

..Despite these consistent observations, the mechanisms by which estrogen regulates angiogenesis under physiological and pathological circumstances have not been defined...

..We conclude that MPTEE is a useful tool for ensuring that myocardial gene therapy performed by direct needle injection results in gene transfer to the LV myocardium...

..We initiated a phase I clinical trial to assess the safety and bioactivity of intramyocardial transfection of plasmid DNA encoding for the angiogenic mitogen vascular endothelial growth factor (ph-VEGF165) in such patients...

..Our study describes the anesthetic considerations and management of such patients treated with a novel approach by using gene therapy to stimulate angiogenesis and improve perfusion to ischemic myocardium...

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..Conclusions-This randomized trial of catheter-based phVEGF-2 myocardial GTx provides preliminary indications regarding the feasibility, safety, and potential efficacy of percutaneous myocardial GTx to human left ventricular myocardium...

..Nevertheless, it seems clear that it is feasible to induce effective therapeutic angiogenesis in selected patients without significant associated toxicity...

..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...

..We hypothesized that estradiol could augment the incorporation of bone marrow (BM)-derived EPCs into sites of ischemia-induced neovascularization, resulting in protection from ischemic injury...

..Because diabetes is associated with impaired wound healing, we tested this hypothesis in a diabetic model of cutaneous wound repair...

..We propose that the attractive vascular and neural guidance functions of netrins offer a unique therapeutic potential...

..This review provides an update of the unique effects of statins on endothelial cells including endothelial progenitor cells as well as highlighting the therapeutic potential of statins beyond their established lipid-lowering effects...

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..This chapter will describe the clinical trial experience to date with delivery of non-viral gene therapy for therapeutic angiogenesis in humans with disabling myocardial ischemia and peripheral vascular disease...

..Taken together, these data indicate that chronic ethanol consumption may negatively influence post angioplasty re-endothelialization thereby contributing to the development of restenosis...

..In this review, we will discuss the currently available bone marrow-derived stem progenitor cells for myocardial repair and focus on the advantages of using recently identified novel bone marrow-derived multipotent stem cells (BMSC)...

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..In contrast, our data suggest that impaired Akt phosphorylation mediates the impairment of angiogenesis associated with HH...

..Diabetic cardiomyopathy (DCM) is characterized by microvascular pathology and interstitial fibrosis, which leads to progressive heart failure; however, the pathogenesis of DCM remains uncertain...

..4+/-0.4, 24.9+/-0.4, and 24.1+/-0.6; P<0.05). CONCLUSIONS: CD34+ cells exhibit superior efficacy for preserving myocardial integrity and function after MI than unselected circulating MNCs...

..However, the roles of estrogen receptors alpha (ER alpha) and beta (ER beta) in EPC biology are largely unknown...

..These data provide evidence for the generation of functional multipotent stem-like cells from terminally differentiated somatic cells without the introduction of retroviral mediated transgenes or ESC fusion...

..This review summarizes the progression of basic, preclinical, and clinical research into the potential use of EPC therapy for cardiovascular regeneration...

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..Thus augmentation of LIF/BMP-2 downstream signaling components or cell type specific precommitment may facilitate the effects of ES cell-based therapies for post-MI myocardial repair and regeneration...

..These findings suggest that angiogenesis in the lungs may participate in the cyclic changes in gas transfer that occur over the menstrual cycle...

..Preclinical studies have indicated that human CD34+ stem cells induce neovascularization in ischemic myocardium, which enhances perfusion and function...

..In summary, our data show that the angiogenic cytokine secretoneurin is up-regulated by hypoxia in muscle cells by hypoxia-inducible factor-1alpha- and basic fibroblast growth factor-dependent mechanisms...

..These observations suggest a potential therapeutic approach for healing wounds in diabetic patients...

..Little is known about the role of TNF-alpha receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling...

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..These findings implicate microvascular damage as the basis for toxic neuropathy and suggest that angiogenic growth factors may constitute a novel treatment for this disorder...

..These results suggest that Notch1 may be a novel therapeutic target for improving angiogenic response and blood flow recovery in ischemic limbs...

..rAAV vectors programmed stable transduction in BM cells in vivo through rapid infection. rAAV appears to represent a useful vector for labeling BM cells ex vivo prior to BMT for analysis of cardiovascular therapeutic purposes...

..The possibility that EPCs could act as reservoirs of cytokines has been implied by several observations; however, a specific role for cytokine delivery has not been identified...

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..This review will discuss gene transfer strategies for therapeutic angiogenesis in critical limb and myocardial ischemia...

..0001). CONCLUSION: These findings indicate that locally delivered SDF-1 augments vasculogenesis and subsequently contributes to ischemic neovascularization in vivo by augmenting EPC recruitment in ischemic tissues...

..This novel therapeutic strategy may merit clinical investigation in patients with lymphedema...

..CONCLUSIONS: These favorable outcomes encourage future clinical trials of catheter-based, intramyocardial transplantation of autologous CD34+ MNCs in the setting of chronic myocardial ischemia...

..The biological significance of this finding was confirmed by augmented limb perfusion in response to US exposure and naked VEGF DNA...

..This enhanced regenerative activity of EPCs by hTERT transfer will provide novel therapeutical strategy for postnatal neovascularization in severe ischemic disease patients...

..Additionally, exposure of ECs to TNF-alpha markedly reduced cyclin A mRNA stability. Targeted disruption of this protein could potentially be a therapeutic strategy to rescue EC proliferation in vivo...

..CONCLUSION: These findings suggest that BM-derived EPCs make a significant contribution to angiogenic growth factor-induced neovascularization that may account for up to 26% of all ECs...

..These results reveal that angiogenesis and vascular permeability induced by VEGF are mediated by mechanisms which ultimately diverge...

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..Here, we studied whether the endogenous Hh pathway, in addition to its functions during embryogenesis, plays a physiological role in muscle regeneration after ischemia in adults...

..A randomized phase III trial is underway that will help determine the efficacy of vascular endothelial growth factor-2 gene transfer in "no-option" patients...

..To our knowledge, this is the first demonstration that a specific population of multipotent human BM-derived stem cells can induce both therapeutic neovascularization and endogenous and exogenous cardiomyogenesis...

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..CONCLUSIONS: Mobilization of endothelial progenitor cells with cytokines potentiates VEGF-2 gene therapy for myocardial ischemia and enhances bone marrow cell incorporation into ischemic myocardium...

..VEGF-2 gene-eluting stents may be considered as a stand-alone or combination therapy...

..CONCLUSIONS: Magnetically labeled EPCs transplanted for therapeutic neovascularization in myocardial ischemia can be visualized with ex vivo MRI at high-field strengths...

..Thus far, no significant deleterious effects or complications have been reported in any studies using BM-derived cells for treatment of various cardiac diseases...

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..Targeted inactivation of JNK1 at arterial injury sites may represent a potential therapeutic intervention for ameliorating TNF-mediated EC dysfunction...

..Further basic research, with improved understanding of the mechanisms governing homing and incorporation of EPCs, will be still necessary to optimize the methodology of the cell therapy...

..In general, these conditions are characterized by local hypovascularity, and the approach to treatment is therefore focused on stimulating neovascularization...