Regulated von Willebrand factor secretion is associated with agonist-specific patterns of cytoskeletal remodeling in cultured endothelial cells

Von Willebrand factor (vWF), an adhesive glycoprotein involved in primary h emostasis, is stored and released from endothelial secretory granules calle d Weibel-Palade bodies. Regulated secretion occurs in reaction either to [C a2+](i)-raising agents (histamine or thrombin) or to cAMP-raising agents (e pinephrine, adenosine, or forskolin). We investigated the pattern of releas e and the cytoskeletal requirements for secretion in response to these 2 cl asses of agonists. Secretion induced by [Ca2+](i)-raising agents involves p eripheral and central granules and is inhibited by colchicine-induced micro tubule disruption. It is accompanied by Rho-dependent stress fiber formatio n and cell retraction. Secretion and remodeling occur in the same individua l cells. However, secretion is potentiated by cytochalasin E and C3 toxin, indicating that stress fiber formation antagonizes vWF secretion. In contra st, vWF secretion induced by cAMP-raising agents involves the release of on ly peripheral granules (implying less VWF release on a per cell basis) and is not inhibited by microtubule disruption, cAMP-mediated secretion is acco mpanied by disruption of stress fibers, strengthening of the cortical actin rim, and preservation of cell-cell contacts. It is unaffected by cytochala sins or C3 toxin. In contrast to [Ca2+](i)-raising agents, cAMP-raising age nts induce secretion without cell retraction/intercellular gap formation. T hus, they are likely to play a physiological role in the regulation of endo thelial vWF secretion and, therefore, of plasma vWF levels.