Pseudopterosins are known anti-inflammatory and anti-microbial agents, isolated from the soft coral, Pseudopterogorgia elisabethae. This study implicates pseudopterosins as activators of cell proliferation in human umbilical vein endothelial cells (HUVEC), a cellular model of angiogenesis. A hydroxypropyl-beta-cyclodextrin (HPbetaCD) formulation of pseudopterosin A (PsA) elicited a 25% increase in cell proliferation (EC50 = 1.34 x10-8 M) in growth factor depleted HUVEC lines. This constitutes a >200 fold increase in potency over DMSO formulations. This increase in specific activity of the drug may result from constraints placed upon PsA orientation in HPbetaCD allowing for more efficient presentation to the receptor. This study demonstrates that the effect of PsA is mediated through inhibition of adenosine A2B receptors which leads to decreased synthesis of cAMP and that this effect can be reversed with a selective A 2 agonist, CV-1808. In addition, evidence is presented that PsA can induce protein kinase B (AKT) phosphorylation which has been shown to activate proliferation via the phosphatidylinositol 3-kinase (PI3K) pathway. Collectively, this indicates that pseudopterosins are promising compounds for adenosine receptor mediated pathologies.