Angiogenesis is an energy demanding process, however, the role of cellular energy pathways and their regulation by extracellular stimuli, especially extracellular nucleotides, remain largely unexplored. Using metabolic inhibitors of glycolysis (2-deoxyglucose, 2-DG) and oxidative phosphorylation (oligomycin, rotenone, and FCCP) we demonstrate that glycolysis and OXPHOS are both essential for angiogenic responses of vasa vasorum endothelial cell (VVEC). Treatment with P2R agonists, ATP and MeSADP, but not P1 receptor agonist, adenosine, increased glycolytic activity in VVEC (measured by extracellular acidification rate and lactate production). Stimulation of glycolysis was accompanied by increased levels of phospho-phosphofructokinase (PFKB3), hexokinase (HK), and GLUT 1, but not lactate dehydrogenase (LDH). Moreover, extracellular ATP and MeSADP, and to a lesser extent, adenosine increased basal and maximal oxygen consumption rates (OCR) in VVEC. These effects were potentiated when the cells were cultured in 20 mM galactose and 5mM glucose compared to 25 mM glucose. Treatment with P2R agonists decreased phosphorylation of pyruvate dehydrogenase (PHD-E1α) and increased succinate dehydrogenase (SDH), cytochrome oxidase (COX IV), and β subunit of F1F0 ATP synthase expression. In addition, P2R stimulation transiently elevated mitochondrial [Ca²⁺], implying involvement of mitochondria in VVEC angiogenic activation. We also demonstrated a critical role of PI3K and Akt pathways in lactate production, pyruvate dehydrogenase complex E1α subunit (PHD-E1α) phosphorylation, and the expression of HK, SDH, and GLUT1 in ATP-stimulated VVEC. Together, our findings suggest that purinergic and metabolic regulation of VVEC energy pathways are essential for VV angiogenesis and may contribute to pathologic vascular remodeling in PH.