![]() ![]() Peripheral arterial disease (PAD) is caused by occlusive atherosclerosis that reduces blood flow to the muscles of the leg(s). 4, 5, 6 The potential consequences of ECs using changes in metabolism pathways other than enhanced glycolysis for angiogenesis are less known. 3 ECs in culture treated with VEGF (vascular endothelial growth factor) and tumor angiogenesis are perhaps the most extensively studied angiogenesis systems, and in these systems the angiogenesis response requires an increase in glycolytic metabolism. 2 During angiogenesis, ECs require an increase in ATP production to meet the energetic demands. 1 Angiogenesis is the growth and formation of new blood vessels from existing vascular structures. Use of the pentose phosphate pathway for therapeutic angiogenesis in PAD may have the advantage of being able to promote the growth of stable, nonleaky, blood vessels.Įven when in a quiescent state, endothelial cells (ECs) require ATP to maintain physiologic function, and the majority of their ATP is produced via glycolytic metabolism, despite ECs being adjacent to the bloodstream and in contact with the sufficient levels of oxygen. In PAD, therapies with VEGFA overexpression will be expected to generate blood vessels that will be leaky and malformed and have a limited ability to provide perfusion to ischemic muscle. In ECs under hypoxia and serum starvation, VEGF 165a significantly increased and miR‐93 decreased EC permeability. MicroRNA‐93 versus control increased reduced nicotinamide adenine dinucleotide phosphate and virtually eliminated the increase in reactive oxygen species. MicroRNA‐93 versus VEGF 165a upregulated glucose‐6‐phosphate dehydrogenase expression and activity, activating the pentose phosphate pathway. In ECs under hypoxia and serum starvation, VEGF 165a versus control significantly upregulated PFKFB3 and glycolysis, whereas miR‐93 versus control demonstrated no increase in PFKFB3 or glycolysis. ECs under hypoxia and serum starvation upregulated PFKFB3. VEGF 165a‐treated Balb/CJ mice post‐HLI showed no improvement in perfusion recovery with ischemic versus nonischemic ECs showing significant increase in glycolysis. MicroRNA‐93‐treated Balb/CJ mice post‐HLI showed better perfusion recovery, with ischemic versus nonischemic ECs showing no increase in glycolysis. Balb/CJ mice generated a poor angiogenic response post‐HLI ischemic versus nonischemic ECs demonstrated significant increase in glycolysis. C57Bl/6J mice generated a robust angiogenic response to HLI, with ECs from ischemic versus nonischemic muscle demonstrating no increase in glycolysis. Reactive oxygen species levels and EC permeability were evaluated. EC metabolism was studied using seahorse assay, and the expression and activity of major metabolism genes were assessed. Post‐HLI perfusion recovery was monitored. Mice following hind‐limb ischemia (HLI) and ECs with, and without, hypoxia and serum starvation were examined with, and without, microRNA‐93 and VEGF 165a. Stroke: Vascular and Interventional Neurology.Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes. ![]() Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB). ![]()
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