doi: 10.1161/01.CIR.0000128595.79378.FA
(Circulation. 2004;109:2487-2491.)
© 2004 American Heart Association, Inc.
Review: Clinical Cardiology: New Frontiers |
Therapeutic Angiogenesis and Vasculogenesis for Ischemic Disease
Part I: Angiogenic Cytokines
From St Elizabeth’s Medical Center, Boston, Mass (D.W.L.), and Department of Molecular Cardiology, University of Frankfurt, Frankfurt, Germany (S.D.).
Correspondence to Douglas W. Losordo, MD, St Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail douglas.losordo{at}tufts.edu
Key Words: angiogenesis • angiogenesis • neovacularization
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Introduction |
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Deprivation of oxygen and nutrients provides a serious threat for tissue viability. Nature’s response to the development of profound tissue ischemia includes the upregulation of angiogenic growth factors and mobilization of circulating cellular elements that together enable development of an accessory vasculature.1 The involved paradigm, not surprisingly, recapitulates many aspects of embryonic circulatory development. Multiple angiogenic factors and inhibitors have been implicated in the formation and correct patterning of functional blood vessels. Although hampered by several ambiguous clinical trials, transfer of genes encoding for proangiogenic factors is still an important therapeutic option to induce vascular growth after critical ischemia. Recent studies provide further evidence that neovascularization is regulated by infiltrating circulation cells, including bone marrow–derived endothelial progenitor cells or inflammatory cells. The use of "cell therapy" for therapeutic vasculogenesis will be discussed in the second part of this review article.
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Gene Therapy for Neovascularization |
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TopIntroductionGene Therapy for...References |
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Candidate Genes: Experimental Evidence
Potential therapeutic genes for improvement of angiogenesis or arteriogenesis include growth factors, which predominantly act on endothelial cells to promote endothelial cell proliferation, migration, and tube-forming activity (Table 1). Concomitantly, most of the growth factors render endothelial cells less sensitive for apoptosis induction. Among the first growth factors identified to improve angiogenesis were members of the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) families. Meanwhile, various isoforms of VEGF have been identified. VEGF-A and its splice variants and VEGF-B preferentially activate the VEGF receptors 1 and 2, whereas VEGF-C and VEGF-D stimulate the VEGF receptors 2 and 3, thereby contributing to lymphangiogenesis. The VEGF receptors 1 and 2 are both expressed on endothelial cells and hematopoietic stem cells. The expression of VEGF receptors on hematopoietic stem cells in particular appears to be of major importance for VEGF-dependent regulation of endothelial progenitor cells (see Part II). More recently, another member of the VEGF family, the placenta-derived growth factor (PlGF), gained increasing attention as a potent direct activator of VEGF receptor 1 and amplifier of VEGF receptor 2 signaling. PlGF increases angiogenesis but also promotes a proinflammatory response leading to acceleration of atherosclerotic lesion formation, probably via activating VEGF receptor 1–positive monocytic cells.2,3
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The members of the FGF family (approximately 23) are multifunctional proteins that bind to various spliced isoforms of the FGF receptors. Activation of the FGF receptors, which are expressed on endothelial cells, smooth muscle cells, and myoblasts, stimulates the proliferation of the respective cell types. In particular, FGF-1, FGF-2, and FGF-4 are highly angiogenic and may act synergistically with VEGF.
Hepatocyte growth factor is another potent multifunctional protein that exerts high proangiogenic activity. It activates its receptor c-met, which is expressed on a variety of cells, including endothelial cells, but also on hematopoietic stem cells. Angiopoietin-1, neurotrophin nerve growth factor, erythropoietin, and insulin-like growth factor (IGF) are additional candidates for therapeutic angiogenesis (Table 1).
Some of the growth factors may enhance tissue regeneration not solely via the proangiogenic activity but also via promotion of stem/progenitor cell mobilization. VEGF, angiopoietin-1, and erythropoietin mobilized endothelial progenitors from the bone marrow.4,5 Interestingly, hepatocyte growth factor in combination with IGF-1 was shown to mobilize tissue-resident cardiac stem cells, resulting in cardiac regeneration.
Several proangiogenic factors may act indirectly via the upregulation of VEGF and possibly other growth factors. This has been shown for the members of the hedgehog (Hh) protein family, which are morphogens regulating epithelial-mesenchymal signaling during several crucial processes of embryonic development. Particularly, sonic hedgehog (Shh) was shown to be a potent inducer of neovascularization after ischemia.6,7 Although the molecular mechanism has not yet been elucidated fully, first studies suggest that Shh acts via upregulating angiopoietins and VEGF.6,7
A second class of candidate genes represents monocyte chemoattractant protein-1 and granulocyte-macrophage colony-stimulating factor, which both act on monocytic cells to promote arteriogenesis.8 Another option is the use of transcription factors, which are known to promote angiogenesis by targeting various proangiogenic genes such as, for example, hypoxia-inducible factor-1
or early growth response protein-1 (EGR-1).9
Other proangiogenic factors activate integrin-dependent pathways to promote angiogenesis. These integrin-activatory proteins include the extracellular matrix protein Del-1, which coordinates integrin expression by homeobox genes.10 Additionally, the family of CCN comprises potent proangiogenic factors such as Cyr61, which binds to avß5, thereby promoting angiogenesis.11 Since integrin-matrix interaction is crucial for controlled vessel development, the temporal regulation of proteins activating or inhibiting integrin signaling is essential for the process of adult neovascularization.
Additionally, regulators of the wnt/frizzled pathway, as shown for the secreted frizzled-related protein FrzA, promote adult angiogenesis.12 This effect was shown to be independent of VEGF.
Finally, Akt/protein kinase B may also represent an attractive therapeutic option, not only for augmenting tissue perfusion but also via more protean effects. Akt expression was long ago shown to induce neovascularization in ischemic tissue13,14 but more recently appeared to restore or preserve tissue integrity in jeopardized myocardium, emphasizing the potential potency of exploiting signaling pathways.
Therapeutic Vessel Growth for Critical Ischemia: Evidence From Human Trials
The large unmet medical need of "no-option" patients—those with disabling ischemia despite optimal medical treatment, after all possibilities for conventional mechanical revascularization have been exhausted—propelled the development of biological revascularization. Initially, these attempts at a new mode of therapy were made with the use of angiogenic growth factors, either as recombinant protein or as gene therapy.
Therapeutic Angiogenesis for Myocardial Ischemia
Preliminary clinical trials established that the results obtained in human subjects with critical limb ischemia15–17 may extend to patients with myocardial ischemia (Table 2).18–20 In particular, investigations of therapeutic neovascularization in patients experiencing functional class III to IV angina refractory to medical therapy and not amenable to conventional revascularization have reported significant symptomatic benefit. Initial studies performed in our laboratory documented that symptomatic improvement in patients with myocardial ischemia was associated with improvement in the outcome of single-photon emission CT (SPECT)-Sestamibi myocardial perfusion imaging19,21; not only was there a reduction in the perfusion deficits associated with pharmacological stress, but large rest defects often resolved as well. These findings constituted objective evidence of improved myocardial perfusion after therapeutic neovascularization, including the possibility that foci of hibernating myocardium might be successfully rescued.
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To determine whether the implications of SPECT imaging could be confirmed by an independent diagnostic technique, we used a novel strategy of catheter-based electromechanical assessment of myocardial perfusion (NOGA system, Biosense-Webster, J&J). This system utilizes electromagnetic field sensors to combine and integrate real-time information from percutaneous, intracardiac electrograms acquired at multiple endocardial locations. The resulting interrogations can be used to distinguish between infarcted and normal myocardium22 and thus permit online assessment of myocardial function and viability.23
The collated electric and mechanical results of percutaneous electromechanical mapping (EMM) provide both an assessment of myocardial viability (ie, the presence of normal versus reduced voltage) and wall motion (presence of normal versus reduced fractional shortening). Validation of intracardiac signal recording and location accuracy has been established previously, both in vitro and in vivo.23,24 Clinical investigations have demonstrated that the mapping capabilities of the NOGA system may be used to distinguish between infarcted and normal myocardium. Gepstein et al23 and Ben-Haim et al24 found significantly lower linear local shortening (LLS) (<4%) and bipolar voltages (<2 mV) in infarcted versus noninfarcted myocardium. Furthermore, comparison with pathological specimens confirmed that the location and extent of infarction could be accurately defined by EMM.
These earlier findings were confirmed by Kornowski et al,22,25 who showed that patients with prior myocardial infarction had reduced unipolar (7.2±2.7 mV) and bipolar (1.4±0.7 mV) voltage recordings compared with patients without prior infarction (19.7±4.4 and 5.8±1.0 mV for unipolar and bipolar recordings, respectively) and that these patients had reduced local endocardial shortening compared with patients without prior infarction. Moreover, Kornowski et al demonstrated that mean voltage and LLS values are highest when measured in myocardial segments with normal perfusion and lowest when measured from segments with fixed perfusion defects; intermediate LLS (4% to 12%) and voltage (
5 mV) recordings were documented for myocardial segments with reversible perfusion defects.
Resolution of rest defects observed in the SPECT scans after gene transfer is particularly intriguing. In this population of severely disabled, no-option patients, the rest defects were presumed to represent sites of myocardial scar associated with the clinical history of myocardial infarction in 13 of 13 patients. Partial or complete resolution of these rest defects after gene transfer is consistent with the notion that these preexisting defects constitute foci of hibernating myocardium26–28 and may have been successfully resuscitated as the result of therapeutic neovascularization.
The corresponding NOGA maps likewise showed reduced evidence of ischemia after gene transfer. EMM provides separate assessments of viability (endocardial voltage recording) and function (linear local shortening). Thus, those areas of the NOGA map that showed viable myocardium with impaired function before gene transfer versus viable myocardium with improved function after gene transfer support the notion that the defects that resolved on the SPECT scans constitute sites of hibernating myocardium26–28 that have been resuscitated as a result of myocardial neovascularization. These findings further confirm that left ventricular EMM may represent an independent diagnostic tool that may be useful for defining the myocardial consequences of improved perfusion.
Percutaneous Gene Transfer for Therapeutic Angiogenesis in Patients With Myocardial Ischemia
The aforementioned clinical findings,29 as well as preliminary studies performed in swine with myocardial ischemia,30 suggested that mapping the extent of ischemia may also be used online to direct percutaneous myocardial gene transfer. Such an adjunct may be particularly advantageous for optimizing low-efficiency strategies such as naked DNA gene transfer, in which EMM may direct injection of naked DNA to ischemic muscle, shown previously to yield higher levels of gene expression.31 We thus designed a pilot study to assess the feasibility, safety, and potential efficacy of catheter-based, percutaneous myocardial gene transfer of naked DNA encoding VEGF-2 administered via a novel needle-injection catheter32 and compared this in single-blind fashion with a mock procedure.
A steerable, deflectable 8F catheter incorporating a 27-guage instrument was advanced percutaneously to the left ventricular myocardium of 6 patients with chronic myocardial ischemia. After safety and evidence of bioactivity were documented with this approach in this small pilot study,33 a second study, this time double-blinded, was performed in 19 patients before it was interrupted by the Food and Drug Administration. In this prospective, randomized pilot study there was a statistically significant greater improvement in Canadian Cardiovascular Society class in the active treatment group compared with control-treated patients; as of this date, nearly all patients have been followed for 1 year with no mortality and no morbidity related to the interventions.34 This has led to plans for a randomized trial of 400 patients to begin in 2004.
Additional evidence for the potential for angiogenic gene therapy is provided by the Angiogenic Gene Therapy (AGENT) study, in which adenovirus encoding FGF-4, administered by a straightforward intracoronary infusion, showed trends toward efficacy in an 84-patient pilot study. Large randomized trials of this therapy, applied in patients with class 2 and 3 angina, are under way.35–48
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Footnotes |
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This is Part I of a 2-part article. Part II will appear in the June 8, 2004, issue of Circulation.
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References |
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|---|
1. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995; 1: 27–30.[CrossRef][Medline] [Order article via Infotrieve]
2. Carmeliet P, Moons L, Luttun A, et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med. 2001; 7: 575–583.[CrossRef][Medline] [Order article via Infotrieve]
3. Luttun A, Tjwa M, Moons L, et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med. 2002; 8: 831–840.[CrossRef][Medline] [Order article via Infotrieve]
4. Heeschen C, Aicher A, Lehmann R, et al. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood. 2003; 102: 1340–1346.
5. Hattori K, Dias S, Heissig B, et al. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med. 2001; 193: 1005–1014.
6. Pola R, Ling LE, Silver M, et al. The morphogen sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat Med. 2001; 7: 706–711.[CrossRef][Medline] [Order article via Infotrieve]
7. Pola R, Ling LE, Aprahamian TR, et al. Postnatal recapitulation of embryonic hedgehog pathway in response to skeletal muscle ischemia. Circulation. 2003; 108: 479–485.
8. Schaper W, Scholz D. Factors regulating arteriogenesis. Arterioscler Thromb Vasc Biol. 2003; 23: 1143–1151.
9. Fahmy RG, Dass CR, Sun LQ, et al. Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth. Nat Med. 2003; 9: 1026–1032.[CrossRef][Medline] [Order article via Infotrieve]
10. Zhong J, Eliceiri B, Stupack D, et al. Neovascularization of ischemic tissues by gene delivery of the extracellular matrix protein Del-1. J Clin Invest. 2003; 112: 30–41.[CrossRef][Medline] [Order article via Infotrieve]
11. Babic AM, Kireeva ML, Kolesnikova TV, et al. CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth. Proc Natl Acad Sci U S A. 1998; 95: 6355–6360.
12. Dufourcq P, Couffinhal T, Ezan J, et al. FrzA, a secreted frizzled related protein, displays a novel angiogenic pathway. Circulation. 2002; 106: 3097–3103.
13. Dimmeler S, Zeiher AM. Akt takes center stage in angiogenesis signaling. Circ Res. 2000; 86: 4–5.
14. Shiojima I, Walsh K. Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res. 2002; 90: 1243–1250.
15. Isner JM, Baumgartner I, Rauh G, et al. Treatment of thromboangiitis obliterans (Buerger’s disease) by intramuscular gene transfer of vascular endothelial growth factor: preliminary clinical results. J Vasc Surg. 1998; 28: 964–73;discussion 73–75.
16. Isner JM, Pieczek A, Schainfeld R, et al. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet. 1996; 348: 370–374.[CrossRef][Medline] [Order article via Infotrieve]
17. Baumgartner I, Pieczek A, Manor O, et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation. 1998; 97: 1114–1123.
18. Schumacher B, Pecher P, vonSpecht BU, et al. Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease. Circulation. 1998; 97: 645–650.
19. Losordo DW, Vale PR, Symes JF, et al. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation. 1998; 98: 2800–2804.
20. Rosengart TK, Lee LY, Patel SR, et al. Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expression VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. Circulation. 1999; 100: 468–474.
21. Hendel RC, Vale PR, Losordo DW, et al. The effects of VEGF-2 gene therapy on rest and stress myocardial perfusion: results of serial SPECT imaging. Circulation. 2000; 102: II–769.
22. Kornowski R, Hong MK, Gepstein L, et al. Preliminary animal and clinical experiences using an electromechanical endocardial mapping procedure to distinguish infarcted from healthy myocardium. Circulation. 1998; 98: 1116–1124.
23. Gepstein L, Hayam G, Ben-Haim SA. A novel method for nonfluoroscopic catheter-based electroanatomical mapping of the heart: in vitro and in vivo accuracy results. Circulation. 1997; 95: 1611–1622.
24. Ben-Haim SA, Osadchy D, Schuster I, et al. Nonfluoroscopic, in vivo navigation and mapping technology. Nat Med. 1996; 2: 1393–1395.[CrossRef][Medline] [Order article via Infotrieve]
25. Kornowski R, Leon MB. Left ventricular electromechanical mapping: current understanding and diagnostic potential. Cathet Cardiovasc Intervent. 1999; 48: 421–429.[CrossRef][Medline] [Order article via Infotrieve]
26. Dilsizian V, Bonow RO. Current diagnostic techniques of assessing myocardial viability in patients with hibernating and stunned myocardium. Circulation. 1993; 87: 1–20.
27. Shen Y-T, Vatner SF. Mechanism of impaired myocardial function during progressive coronary stenosis in conscious pigs: hibernation versus stunning? Circ Res. 1995; 76: 479–488.
28. Wijns W, Vatner SF, Camici PG. Hibernating myocardium. N Engl J Med. 1998; 3: 173–181.
29. Vale PR, Losordo DW, Milliken CE, et al. Left ventricular electromechanical mapping to assess efficacy of phVEGF(165) gene transfer for therapeutic angiogenesis in chronic myocardial ischemia. Circulation. 2000; 102: 965–974.
30. Vale PR, Losordo DW, Tkebuchava T, et al. Catheter-based myocardial gene transfer utilizing nonfluoroscopic electromechanical left ventricular mapping. J Am Coll Cardiol. 1999; 34: 246–254.
31. Tsurumi Y, Takeshita S, Chen D, et al. Direct intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion. Circulation. 1996; 94: 3281–3290.
32. Vale PR, Losordo DW, Milliken CE, et al. Images in cardiovascular medicine: percutaneous myocardial gene transfer of phVEGF-2. Circulation. 1999; 100: 2462–2463.
33. Vale PR, Losordo DW, Milliken CE, et al. Randomized, single-blind, placebo-controlled pilot study of catheter-based myocardial gene transfer for therapeutic angiogenesis using left ventricular electromechanical mapping in patients with chronic myocardial ischemia. Circulation. 2001; 103: 2138–2143.
34. Losordo DW, Vale PR, Hendel RC, et al. Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation. 2002; 105: 2012–2018.
35. Stegmann TJ, Hoppert T, Schneider A, et al. Induction of myocardial neoangiogenesis by human growth factors: a new therapeutic option in coronary heart disease. Herz. 2000; 25: 589–599.[CrossRef][Medline] [Order article via Infotrieve]
36. Sellke FW, Laham RJ, Edelman ER, et al. Therapeutic angiogenesis with basic fibroblast growth factor: technique and early results. Ann Thorac Surg. 1998; 65: 1540–1544.
37. Laham RJ, Sellke FW, Edelman ER, et al. Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: results of a phase 1 randomized, double-blind, placebo-controlled trial. Circulation. 1999; 100: 1865–1871.
38. Udelson JE, Dilsizian V, Laham RJ, et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 improves stress and rest myocardial perfusion abnormalities in patients with severe symptomatic chronic coronary artery disease. Circulation. 2000; 102: 1605–1610.
39. Laham RJ, Rezaee M, Post M, et al. Intrapericardial delivery of fibroblast growth factor-2 induces neovascularization in a porcine model of chronic myocardial ischemia. J Pharmacol Exp Ther. 2000; 292: 795–802.
40. Unger EF, Goncalves L, Epstein SE, et al. Effects of a single intracoronary injection of basic fibroblast growth factor in stable angina pectoris. Am J Cardiol. 2000; 85: 1414–1419.[CrossRef][Medline] [Order article via Infotrieve]
41. Simons M, Annex BH, Laham RJ, et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation. 2002; 105: 788–793.
42. Hendel RC, Henry TD, Rocha-Singh K, et al. Effect of intracoronary recombinant human vascular endothelial growth factor on myocardial perfusion: evidence for a dose-dependent effect. Circulation. 2000; 101: 118–121.
43. Henry TD, Rocha-Sing K, Isner JM, et al. Intracoronary administration of recombinant human vascular endothelial growth factor to patients with coronary artery disease. Am Heart J. 2001; 142: 872–880.[CrossRef][Medline] [Order article via Infotrieve]
44. Henry TD, Abraham JA. Review of preclinical and clinical results with vascular endothelial growth factors for therapeutic angiogenesis. Curr Intervent Cardiol Rep. 2000; 2: 228–241.[Medline] [Order article via Infotrieve]
45. Henry TD, Annex BH, McKendall GR, et al. The VIVA trial: vascular endothelial growth factor in ischemia or vascular angiogenesis. Circulation. 2003; 107: 1359–1365.
46. Rosengart TK, Lee LY, Port JL, et al. Video assisted epicardial delivery of angiogenic gene therapy to the human myocardium utilizing an adenovirus vector encoding for VEGF121. Circulation. 1999; 100: I-770.
47. Fortuin FD, Vale P, Losordo DW, et al. One-year follow-up of direct myocardial gene transfer of vascular endothelial growth factor-2 using naked plasmid deoxyribonucleic acid by way of thoracotomy in no-option patients. Am J Cardiol. 2003; 92: 436–439.[CrossRef][Medline] [Order article via Infotrieve]
48. Grines CL, Watkins MW, Helmer G, et al. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation. 2002; 105: 1291–1297.
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L. Zentilin, S. Tafuro, S. Zacchigna, N. Arsic, L. Pattarini, M. Sinigaglia, and M. Giacca Bone marrow mononuclear cells are recruited to the sites of VEGF-induced neovascularization but are not incorporated into the newly formed vessels Blood, May 1, 2006; 107(9): 3546 - 3554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rafii and D. Lyden Contribution of Hematopoietic and Vascular Progenitor Cells to the Neoangiogenic Niche Am. Assoc. Cancer Res. Educ. Book, April 1, 2006; 2006(1): 181 - 185. [Full Text] [PDF]
|
|
|
|
|
|
P. Anversa, J. Kajstura, A. Leri, and R. Bolli Life and Death of Cardiac Stem Cells: A Paradigm Shift in Cardiac Biology Circulation, March 21, 2006; 113(11): 1451 - 1463. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Muller-Ehmsen, A. Schmidt, B. Krausgrill, R. H. G. Schwinger, and W. Bloch Role of erythropoetin for angiogenesis and vasculogenesis: from embryonic development through adulthood Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H331 - H340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Thum, D. Tsikas, S. Stein, M. Schultheiss, M. Eigenthaler, S. D. Anker, P. A. Poole-Wilson, G. Ertl, and J. Bauersachs Suppression of Endothelial Progenitor Cells in Human Coronary Artery Disease by the Endogenous Nitric Oxide Synthase Inhibitor Asymmetric Dimethylarginine J. Am. Coll. Cardiol., November 1, 2005; 46(9): 1693 - 1701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Leri, J. Kajstura, and P. Anversa Cardiac Stem Cells and Mechanisms of Myocardial Regeneration Physiol Rev, October 1, 2005; 85(4): 1373 - 1416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. H. Patel, H. Kimura, C. R. Weiss, G. L. Semenza, and L. V. Hofmann Constitutively active HIF-1{alpha} improves perfusion and arterial remodeling in an endovascular model of limb ischemia Cardiovasc Res, October 1, 2005; 68(1): 144 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. C. Sasso, D. Torella, O. Carbonara, G. M. Ellison, M. Torella, M. Scardone, C. Marra, R. Nasti, R. Marfella, D. Cozzolino, et al. Increased Vascular Endothelial Growth Factor Expression But Impaired Vascular Endothelial Growth Factor Receptor Signaling in the Myocardium of Type 2 Diabetic Patients With Chronic Coronary Heart Disease J. Am. Coll. Cardiol., September 6, 2005; 46(5): 827 - 834. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tsutsumi and D. W. Losordo Double Face of VEGF Circulation, August 30, 2005; 112(9): 1248 - 1250. [Full Text] [PDF]
|
|
|
|
|
|
G. P. Fadini, M. Miorin, M. Facco, S. Bonamico, I. Baesso, F. Grego, M. Menegolo, S. V. de Kreutzenberg, A. Tiengo, C. Agostini, et al. Circulating Endothelial Progenitor Cells Are Reduced in Peripheral Vascular Complications of Type 2 Diabetes Mellitus J. Am. Coll. Cardiol., May 3, 2005; 45(9): 1449 - 1457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Madeddu Therapeutic angiogenesis and vasculogenesis for tissue regeneration Exp Physiol, May 1, 2005; 90(3): 315 - 326. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S. Werner, E. Jandt, A. Krack, G. Schwarz, O. Mutschke, F. Kuethe, M. Ferrari, and H. R. Figulla Growth Factors in the Collateral Circulation of Chronic Total Coronary Occlusions: Relation to Duration of Occlusion and Collateral Function Circulation, October 5, 2004; 110(14): 1940 - 1945. [Abstract] [Full Text] [PDF]
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