Myocardial angiogenesis

Direct laser-assisted myocardial revascularization (DMR) is an approved technique in the US, Europe, and parts of Asia to create numerous myocardial channels. This results in the induction of a massive inflammatory reaction, which in turn induces angiogenesis. The other FDA-approved pro-angiogenic therapy is the use of recombinant human platelet-derived growth factor (Regranex) for use in the treatment of diabetic neuropathic foot ulcer s. 

VSMCs 4. Angiogenesis. 5. Dysregulation of MMPs myocardial necrosis. 

While the role of PHD inhibitors in the treatment of anemia is now validated, therapeutic validation is less certain in other HIF-associated pathologies such as wound healing, ulcerative colitis, therapeutic angiogenesis, and treatment of acute ischemic events such as myocardial ischemia and stroke. All of these indications are supported by a compelling array of in vitro and in vivo preclinical studies but their utility in the clinical setting remains to be evaluated and represents exciting possibilities for the future of small-molecule inhibitors of PHD enzymes. 

Nagays, N., Fujii, T., Iwase, T., et al (2004) Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis. Am J Physiol Heart Circ Physiol 287, H2670-H2676. 

In a proof-of-concept study in which Saito et al. [60] intravenously injected LacZ reporter gene-transfected MSCs into healthy rats, the MSCs preferentially engrafted in the bone marrow. When injected into rats subjected to repetitive periods of ischemia/reperfusion, however, the MSCs engrafted in the infarcted regions of the heart, where they participated in angiogenesis and expressed cardio-myocyte-specific proteins. When injected into rats 10 days after myocardial injury, MSCs preferentially homed to damaged myocardium. 

The feasibility and efficacy of granulocyte-colony stimulating factor (G-CSF) therapy and subsequent intracoronary infusion of collected peripheral blood stem cells were prospectively investigated in the MAGIC randomized clinical trial [137], which showed improved cardiac function and promotion of angiogenesis in myocardial infarction patients. 

Adenosine 3 receptor ADORA3 Agonism Immunosuppression, hypotension, anti-ischaemic (cardioprotective), pro-ischaemic (cerebral), cell necrosis, cell proliferation and angiogenesis. Antagonism might cause myocardial ischaemia, proinflammatory effects, hypertension and interfere with the regulation of cell growth. 

Nanoparticles formulated with PLGA have been shown to be rapidly uptaken by the endothelial cells, the uptake was shown to depend on the nanoparticle concentration and the particles where mainly shown to localize in the cytoplasm (207). These nanoparticles were also shown to be biocompatible with the cells with no effect on cell viability (207). This is important due to the fact that endothelium is an important target for gene therapy in a number of disorders including angiogenesis, atherosclerosis, tumor growth, myocardial infarction, limb and cardiac ischemia, restenosis (207). 

Losordo, D.W., Vale, P.R., Symes, J.F., Dunnington, C.H., Esakof, D.D., Maysky, M. et al. (1998) Gene therapy for myocardial angiogenesis initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation, 98, 2800-2804. 

Boekstegers, P. (2001) Perspectives on selective retroinfusion of coronary veins as an alter-native approach for myocardial gene transfer and angiogenesis. J. Inv. Cardiol., 13, 339-342.. ... 

The kuopio angiogenesis trial (KAT), a phase II clinical trial involving 103 patients, used adenovirus gene transfer for VEGF mainly in stented patients, At six months, no detectable difference was seen in restenosis rates compared with controls, but there was a significant improvement in myocardial perfusion (47). 

I Pearlman JD, Hibberd MG, Chuang ML, et al. Magnetic resonance mapping demonstrates benefits of VEGF-induced myocardial angiogenesis. Nat Med 1995 I (10) 1085-1089,... 

Vale PR, Losordo DW Milliken CE, McDonald MC, Gravelin LM, Curry CM, 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. 

The efficacy of gene transfer approaches to therapeutic angiogenesis is now being tested in clinical trials. Controlled phase II trials are providing positive but not definitive results. Gene therapy appears to be safe based on these data. Hard clinical endpoints, such as mortality, myocardial infarction, and the need for revascularization are lacking, as is long-term follow-up. 

In numerous animal models, it has reportedly promoted angiogenesis, improved myocardial perfusion, and acutely improved endothelial vasodilatory function. In the present study, we report the impact of the administration of recombinant FGF-2 (rFGF-2) on stress and rest myocardial perfusion using gated SPECT myocardial perfusion imaging in a phase I trial in humans with advanced symptomatic coronary artery disease. 

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. 

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