A pivotal autocrine mechanism following endothelial cell activation is the release of angiopoietin-2 (Ang-2) which subsequently antagonizes the binding of Ang-1 to the endothelial cell Tie-2 receptor hence sensitizing them to pro-angiogenic or pro-inflammatory stimuli. In this context, we noted that hypertension in mice reduces the abundance of Ang-2 stored in arterial endothelial cells, and hypothesized that this Ang-2 release depends on an increase in circumferential wall tension or stretch - a hallmark of hypertension. In fact, stretching isolated perfused mouse arteries or human cultured endothelial cells triggered rapid Ang-2 release. In cultured endothelial cells this was preceded by a transient rise in intracellular free calcium, abrogated through calcium chelation and accompanied by a decrease in Tie-2 phosphorylation. On the functional level, the local rise in Ang-2 augmented vascular cell adhesion molecule-1 (VCAM-1) expression in response to interleukin-8 (IL-8). Interestingly, Ang-1 abolished the stretch-induced Ang-2 release and VCAM-1 expression. Subsequent analyses indicated that pre-treatment with Ang-1 robustly inhibits any stretch-induced calcium response in endothelial cells. Collectively, these results indicate that an increase in circumferential wall tension facilitates the release of Ang-2 from endothelial cell storages that can be antagonized by the attenuation of the intracellular calcium release through Ang-1.