We investigated the role of the p38 mitogen-activated protein kinase (p38 MAPK) in the PDGF-BB-induced cytoskeleton remodeling that occurs during the migration of porcine aortic smooth muscle cells (SMC). We showed that p38 MAPK controlled the polymerization of actin that is required for PDGF-induced lamellipodia formation and migration. To investigate the mechanism of action of p38 MAPK, we explored its cellular localization and that of its indirect substrate, the heat shock protein Hsp27, during SMC spreading on fibronectin in the presence and absence of PDGF. Spreading of SMC on fibronectin activated p38 MAPK in a sustained manner only in the presence of PDGF. In these conditions, Hsp27 and p38 MAPK were localized all over the lamellipodia. A transiently phosphorylated form of p38 MAPK was observed at the leading edge, whereas p38 MAPK remained phosphorylated at the base of the lamellipodia. Phosphorylated Hsp27 was excluded from the leading edge and restricted to the base of the lamellipodia. These results were confirmed by Triton X-100 extraction of particulate membrane fraction. Displacement of Hsp27 from the leading edge by cytochalasin D treatment suggests that nonphosphorylated Hsp27 caps barbed ends in vivo. Our data indicate that nonphosphorylated Hsp27 might contribute to the formation of a short, branched actin network at the leading edge, whereas phosphorylated Hsp27 might stabilize the actin network at the base of lamellipodia, which is composed of long, unbranched actin filaments.

Hemostasis and pathological thrombus formation are dynamic processes that require multiple adhesive receptor-ligand interactions, with blood platelets at the heart of such events. Many studies have contributed to shed light on the importance of von Willebrand factor (VWF) interaction with its platelet receptors, glycoprotein (GP) Ib-IX-V and αIIbβ3 integrin, in promoting primary platelet adhesion and aggregation following vessel injury. This review will recapitulate our current knowledge on the subject from the rheological aspect to the spatio-temporal development of thrombus formation. We will also discuss the signaling events generated by VWF/GPIb-IX-V interaction, leading to platelet activation. Additionally, we will review the growing body of evidence gathered from the recent development of pathological mouse models suggesting that VWF binding to GPIb-IX-V is a promising target in arterial and venous pathological thrombosis. Finally, the pathological aspects of VWF and its impact on platelets will be addressed.