Vascular Endothelial Growth Factor-B Induces Myocardium-Specific Angiogenesis and Arteriogenesis via Vascular Endothelial Growth Factor Receptor-1– and Neuropilin Receptor-1–Dependent Mechanisms

Abstract

Background-New revascularization therapies are urgently needed for patients with severe coronary heart disease who lack conventional treatment options. Methods and Results-We describe a new proangiogenic approach for these no-option patients using adenoviral (Ad) intramyocardial vascular endothelial growth factor (VEGF)-B 186 gene transfer, which induces myocardium-specific angiogenesis and arteriogenesis in pigs and rabbits. After acute infarction, AdVEGF-B 186 increased blood vessel area, perfusion, ejection fraction, and collateral artery formation and induced changes toward an ischemia-resistant myocardial phenotype. Soluble VEGF receptor-1 and soluble neuropilin receptor-1 reduced the effects of AdVEGF-B 186 , whereas neither soluble VEGF receptor-2 nor inhibition of nitric oxide production had this result. Key Words: angiogenesis Ⅲ gene therapy Ⅲ metabolism Ⅲ myocardial infarction S evere coronary heart disease is still a leading cause of death in developed countries in spite of improved management of risk factors and more effective treatments. It is estimated that approximately 5 million people in the United States and the European Union have ischemic heart disease; however, a steadily increasing number of patients fall into a category in which currently available revascularization techniques cannot be applied. This is especially true of elderly patients who have had multiple bypass and stenting operations. 1 It is estimated that these patients represent up to 3% to 5% of all patients in specialty cardiology clinics. Thus, there is a clear need to develop efficient, minimally invasive procedures for the treatment of these no-option patients. Clinical Perspective p 856Therapeutic vascular growth (ie, angiogenesis and arteriogenesis) with genes or proteins has been suggested as an alternative approach for the treatment of these patients. 2 Vascular endothelial growth factors (VEGFs) are potent inducers of vascular growth via binding to 3 tyrosine kinase receptors (VEGFRs). VEGFR-2 is the main regulator of angiogenesis, exerting its function via nitric oxide production, whereas the role of VEGFR-1 is far less defined. 3 VEGF-B 4 and placental growth factor (PlGF) 3 share structural and functional characteristics and bind to VEGFR-1, whereas VEGF-A 5 binds to both VEGFR-1 and VEGFR-2. 846 Circulation

Vascular endothelial growth factor-B: Impact on physiology and pathology

“…For example, in the two studies, 70,77 the common myocardial-specific angiogenesis and arteriogenes activity were observed. Whereas, in rabbits and the pigs, 77 the aggrandizement of FATP4 expression and lipids and glycogen accumulation in the myocardium were observed; while there is no difference in cardiac or skeletal muscle FAs influx between the VEGF-B transgenic, gene-deleted and wild type rats. 70 It is important to note that FAs and TGs levels were reduced in the transgenic rat.…”

“…97 The L-NAME did not cancel VEGF-B activity, emphasizing the uniqueness of VEGF-B. To explain these different effects, Ad-VEGF-B 186 and Ad-PlGF might signal through different receptor binding sites and/or structural variants, or alternatively, acted by recruiting distinct co-receptors to the signaling complex, 13 thereby inducing various downstream events, 77 which was verified since VEGF-B did not rescue development in PlGF deficiency mice. 95 In comparison, the VEGF-B has marked superiority over its family members.…”

“…For example, the transgenic mice developed an invalid cardiac hypertrophy due to an enlarged size of the cardiomyocytes but lacked an arteriogenic phenotype, failed to compromise heart ability; 15 however, the cardiac hypertrophy observed in the transgenic or AAV-VEGF-B overexpression rats could be attributed to the coronary tree expanding and reprogram of the cardiomyocyte energy substrate utilization from FAs oxidation towards glucose oxidation. 70 In turn, the alike manifold lipid and glycogen accumulation in the myocardium caused the metabolic changes, 77 cardiac hypertrophy, 70 mitochondrial lipotoxicity and the consecutive mouse death, 15 respectively in three distinct studies.…”

“…18 , 77 Several factors had been proposed to participate, such as the diversity of genetic background, VEGF-B isoforms or means for VEGF-B overproduction (recombinant proteins, naked plasmid DNA or adenoviral vectors). 89 In this respect, adenoviruses and AAV vectors administration represented the most efficient vectors to transfer genes into the adult myocardium and ensured a prolonged effect.…”

Cardiac gene therapy in large animals: bridge from bench to bedside

“…Whereas permanent occlusion of the coronary blood flow can be easily obtained by surgical coronary ligation, the endovascular approach requires implantation of the embolic coil. 8,15 The infarcted area and its border zone are primary targets for evaluating angiogenic gene therapies. In addition, as left ventricular remodeling and impaired cardiac function result in these models, they are preferred for various types of other cardiac gene therapy evaluations as well, provided the size of the infarction is large enough to cause chronic heart failure.…”