In vitro angiogenic effects of pancreatic bile salt-dependent lipase.

OBJECTIVE: Bile salt-dependent lipase (BSDL), a lipolytic enzyme secreted in the duodenum by pancreatic acinar cells, has been detected in the serum of all patients and in atheromatous plaque, suggesting its potential implication in vascular pathophysiology. METHODS AND RESULTS: In vitro pancreatic BSDL evokes human umbilical vein endothelial cell (HUVEC) proliferation and chemotactic migration. BSDL at mitogen concentration is capable to heal wounded HUVEC monolayer and to promote capillary network formation. HUVEC proliferation depends on the displacement of basic fibroblast growth factor and vascular endothelial growth factor from the extracellular matrix and the activation of extracellular signal-regulated kinases (ERK1/2), p38 mitogen-activated protein kinase, and focal adhesion kinase signaling pathways. CONCLUSIONS: For the first time to our knowledge, it is suggested that circulating BSDL could be involved in pathophysiological angiogenesis. We delineate the in vitro effects of pancreatic BSDL on endothelial cells, and we show that BSDL promotes proliferation, migration, capillary network formation, and wound-healing of HUVECs via the displacement of bFGF and VEGF from the ECM, suggesting that BSDL could be involved in angiogenesis.

Antiangiogenic activity of paclitaxel is associated with its cytostatic effect, mediated by the initiation but not completion of a mitochondrial apoptotic signaling pathway.

Angiogenesis is a critical event in tumor growth and metastasis, which can be inhibited by conventional anticancer drugs such as the microtubule-damaging agent paclitaxel (Taxol). In this study, we investigate the mechanism of action of paclitaxel on human endothelial cells. We characterize two distinct effects of paclitaxel on human umbilical vein endothelial cell and human microvascular endothelial cell-1 proliferation according to drug concentration: a cytostatic effect at low concentrations and a cytotoxic effect at concentrations > or =10 nmol/L. The cytotoxic effect involves signaling pathways similar to those described in tumor cells (i.e., microtubule network disturbance, G(2)-M arrest, increase in Bax/Bcl-2 ratio, and mitochondria permeabilization) that result in apoptosis. In sharp contrast, the cytostatic effect involves an inhibition of endothelial cell proliferation without apoptosis induction and without any structural modification of the microtubule network. This cytostatic effect is due to a slowing of the cell cycle rather than to an arrest in a specific phase of the cell cycle. In addition, paclitaxel, at cytostatic concentrations, early initiates an apoptotic signaling pathway associated with increases in the mitochondrial reducing potential, mitochondrial membrane potential, p53 expression, and Bax/Bcl-2 ratio. However, this apoptotic pathway is stopped upstream of mitochondria permeabilization and it does not lead to endothelial cell death. Finally, we found that paclitaxel inhibits endothelial cell morphogenesis on Matrigel at all tested concentrations. In conclusion, we describe the mechanism of action of low concentrations of paclitaxel related to the antiangiogenic properties of this drug.

Pancreatic bile salt-dependent lipase induces smooth muscle cells proliferation.

BACKGROUND: Because bile salt-dependent lipase (BSDL), an enzyme secreted by the pancreatic acinar cells and associated with LDL in circulating blood, also locates with smooth muscle cells (SMCs) in atherosclerotic lesions, we aimed to investigate its effects on SMCs. METHODS AND RESULTS: Immunohistochemical experiments allowed us to detect an expression of BSDL in atherosclerotic lesions from hypercholesterolemic monkeys and from human arteries. BSDL was found to be associated with SMCs but not with macrophages. BSDL was significantly mitogenic for cultured SMCs. This effect was inhibited by heparin and anti-BSDL antibodies, whereas heat-denaturated and diisopropylfluorophosphate-treated BSDL were inefficient. The mitogenic effect of BSDL was associated with an activation of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway, which was inhibited by heparin, and involved several mechanisms, among them diacylglycerol and oleic acid production as well as a rapid basic fibroblast growth factor release. CONCLUSIONS: Circulating BSDL is associated with SMCs within the intimal arteria and may trigger SMC proliferation, which could contribute to the development of atherosclerotic lesions.