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      • Record: found
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      PlGF Repairs Myocardial Ischemia through Mechanisms of Angiogenesis, Cardioprotection and Recruitment of Myo-Angiogenic Competent Marrow Progenitors

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          Abstract

          Rationale

          Despite preclinical success in regenerating and revascularizing the infarcted heart using angiogenic growth factors or bone marrow (BM) cells, recent clinical trials have revealed less benefit from these therapies than expected.

          Objective

          We explored the therapeutic potential of myocardial gene therapy of placental growth factor (PlGF), a VEGF-related angiogenic growth factor, with progenitor-mobilizing activity.

          Methods and Results

          Myocardial PlGF gene therapy improves cardiac performance after myocardial infarction, by inducing cardiac repair and reparative myoangiogenesis, via upregulation of paracrine anti-apoptotic and angiogenic factors. In addition, PlGF therapy stimulated Sca-1 +/Lin − (SL) BM progenitor proliferation, enhanced their mobilization into peripheral blood, and promoted their recruitment into the peri-infarct borders. Moreover, PlGF enhanced endothelial progenitor colony formation of BM-derived SL cells, and induced a phenotypic switch of BM-SL cells, recruited in the infarct, to the endothelial, smooth muscle and cardiomyocyte lineage.

          Conclusions

          Such pleiotropic effects of PlGF on cardiac repair and regeneration offer novel opportunities in the treatment of ischemic heart disease.

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          Most cited references25

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          Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1.

          Aernout Luttun, Marc Tjwa, Lieve Moons … (2002)
          The therapeutic potential of placental growth factor (PlGF) and its receptor Flt1 in angiogenesis is poorly understood. Here, we report that PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to vascular endothelial growth factor (VEGF). An antibody against Flt1 suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in autoimmune arthritis. Anti-Flt1 also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not attributable to reduced plaque neovascularization. Inhibition of VEGF receptor Flk1 did not affect arthritis or atherosclerosis, indicating that inhibition of Flk1-driven angiogenesis alone was not sufficient to halt disease progression. The anti-inflammatory effects of anti-Flt1 were attributable to reduced mobilization of bone marrow-derived myeloid progenitors into the peripheral blood; impaired infiltration of Flt1-expressing leukocytes in inflamed tissues; and defective activation of myeloid cells. Thus, PlGF and Flt1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation.
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            Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor.

            G Viglietto, G Persico, V Guerriero … (1991)
            A human cDNA coding for a protein related to the vascular permeability factor (VPF) was isolated from a term placenta cDNA library; we therefore named its product placenta growth factor (PlGF). PlGF is a 149-amino-acid-long protein and is highly homologous (53% identity) to the platelet-derived growth factor-like region of human VPF. Computer analyses reveal a putative signal peptide and two probable N-glycosylation sites in the PlGF protein, one of which is also conserved in human VPF. By using N-glycosidase F, tunicamycin, and specific antibodies produced in both chicken and rabbit, we demonstrate that PlGF, derived from transfected COS-1 cells, is actually N-glycosylated and secreted into the medium. In addition, PlGF, like VPF, proves to be a dimeric protein. Finally, a conditioned medium from COS-1 cells containing PlGF is capable of stimulating specifically the growth of CPA, a line of endothelial cells, in vitro.
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              Formation of human myocardium in the rat heart from human embryonic stem cells.

              Michael A. Laflamme, Joseph B. Gold, Chunhui Xu … (2005)
              Human embryonic stem cells (hESCs) offer the opportunity to replenish cells lost in the postinfarct heart. We explored whether human myocardium could be generated in rat hearts by injecting differentiated cardiac-enriched hESC progeny into the left ventricular wall of athymic rats. Although initial grafts were predominantly epithelial, noncardiac elements were lost over time, and grafts consisted predominantly of cardiomyocytes by 4 weeks. No teratomatous elements were observed. Engrafted cardiomyocytes were glycogen-rich and expressed expected cardiac markers including beta-myosin heavy chain, myosin light chain 2v, and atrial natriuretic factor. Heat-shock treatment improved graft size approximately threefold. The cardiac implants exhibited substantial angiogenesis, both recipient and graft derived. Importantly, there was greater proliferation in human cardiomyocytes than previously seen in rodent-derived cardiomyocytes: 14.4% of graft cardiomyocytes expressed the proliferation marker Ki-67, and 2.7% incorporated the thymidine analog BrdU 4 weeks after transplantation. This proliferation was associated with a sevenfold increase in graft size over the 4-week interval. Thus, hESCs can form human myocardium in the rat heart, permitting studies of human myocardial development and physiology and supporting the feasibility of their use in myocardial repair.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2011
                Publication date (Electronic): 28 September 2011
                Volume: 6
                Issue: 9
                Electronic Location Identifier: e24872
                Affiliations
                [1 ]Stem Cell Translational Research, Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
                [2 ]Department of Cardiovascular Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
                [3 ]The Center for Transgene Technology and Gene Therapy, K.U.Leuven, Leuven, Belgium
                [4 ]Department of Transgene Technology and Gene Therapy, VIB, Leuven, Belgium
                [5 ]Department of Regenerative Medicine Science, Tokai University School of Medicine, Isehara, Japan
                Leiden University Medical Center, The Netherlands
                Author notes

                Conceived and designed the experiments: HI AK PC TA. Performed the experiments: HI MT MH SH AO TM. Analyzed the data: HI AK SS. Contributed reagents/materials/analysis tools: MT SH. Wrote the paper: HI AK PC TA.

                Article
                Publisher ID: PONE-D-11-08324
                DOI: 10.1371/journal.pone.0024872
                PMC ID: 3182165
                PubMed ID: 21969865
                SO-VID: 2f9f12a4-00b7-4dc1-a5ff-9d3ddbd88e0e
                Copyright © Iwasaki et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 25 April 2011
                Date accepted : 22 August 2011
                Page count
                Pages: 14
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Developmental Biology
                Subject: Stem Cells
                Subject: Adult Stem Cells
                Subject: Hematopoietic Stem Cells
                Subject: Induced Pluripotent Stem Cells
                Subject: Molecular Cell Biology
                Subject: Cellular Types
                Subject: Stem Cells
                Subject: Adult Stem Cells
                Subject: Hematopoietic Stem Cells
                Subject: Induced Pluripotent Stem Cells
                Subject: Medicine
                Subject: Cardiovascular
                Subject: Myocardial Infarction
                Subject: Clinical Genetics
                Subject: Gene Therapy

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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