CD40 ligand (CD40L, CD154), a transmembrane protein structurally related to the cytokine TNF-alpha, was originally identified on stimulated CD4+ T cells, and later on stimulated mast cells and basophils. Interaction of CD40L on T cells with CD40 on B cells is of paramount importance for the development and function of the humoral immune system. CD40 is not only constitutively present on B cells, but it is also found on monocytes, macrophages and endothelial cells, suggesting that CD40L has a broader function in vivo. We now report that platelets express CD40L within seconds of activation in vitro and in the process of thrombus formation in vivo. Like TNF-alpha and interleukin-1, CD40L on platelets induces endothelial cells to secrete chemokines and to express adhesion molecules, thereby generating signals for the recruitment and extravasation of leukocytes at the site of injury. Our results indicate that platelets are not only involved in haemostasis but that they also directly initiate an inflammatory response of the vessel wall.

Endothelial cells of the arterial vascular system and the heart contain straight actin filament bundles, of which there are few, if any, in the venous endothelium. Since stress fibre-containing endothelial cells within the vascular system tend to be located at sites exposed to particularly high shear stress of blood flow, we have investigated, in an experimental rheological system (Fig. 1), the response of the endothelial actin filament skeleton to controlled levels of fluid shear stress. Here we report that endothelial stress fibres can be induced by a 3-h exposure of confluent monolayer cultures of human vascular endothelium to a fluid shear stress of 2 dynes cm-2, approximately the stress occurring in human arteries in vivo. Fourfold lower levels of shear stress that normally occur only in veins, had no significant effect on the endothelial actin filament system. The formation of endothelial stress fibres in response to critical levels of fluid shear stress is probably a functionally important mechanism that protects the endothelium from hydrodynamic injury and detachment.

Endothelial cells (EC) play a central role in inflammatory immune

Background-Low-dose dobutamine challenge (DSMR) by MRI was compared with delayed enhancement imaging with Gd-DTPA (SCAR) as a predictor of improvement of wall motion after revascularization (RECOVERY). Methods and Results-In 29 patients with coronary artery disease (68Ϯ7 years of age, 2 women, 32Ϯ8% ejection fraction), wall motion was evaluated semiquantitatively by MRI before and 3 months after revascularization. SCAR and DSMR were performed before revascularization. The transmural extent of scar was assessed semiquantitatively.

Abstract-Migration of endothelial cells (EC) is a key event in angiogenesis that contributes to neovascularization in diabetic vasculopathy. Leptin induces angiogenesis and is elevated in obesity and hyperinsulinemia. The antidiabetic thiazolidinediones (TZD) inhibit leptin gene expression and vascular smooth muscle cell migration through activation of the peroxisome proliferator-activated receptor-␥ (PPAR␥). This study investigates the role of leptin in EC migration, the chemotactic signaling pathways involved, and the effects of the TZD-PPAR␥ ligands troglitazone (TRO) and ciglitazone (CIG) on EC migration. We demonstrate that leptin induces EC migration. Because activation of two signaling pathways, the phosphatidylinositol-3 kinase (PI3K)3 Akt3eNOS and the ERK1/2 MAPK pathway, is known to be involved in cell migration, we used the pharmacological inhibitors wortmannin and PD98059 to determine if chemotactic signaling by leptin involves Akt or ERK1/2, respectively. Both wortmannin and PD98059 significantly inhibited leptin-induced migration. Treatment with the TZD-PPAR␥-ligands TRO and CIG significantly inhibited the chemotactic response toward leptin. Both PPAR␥-ligands inhibited leptin-stimulated Akt and eNOS phosphorylation, but neither attenuated ERK 1/2 activation in response to leptin. The inhibition of Akt-phosphorylation was accompanied by a PPAR␥-ligand-mediated upregulation of PTEN, a phosphatase that functions as a negative regulator of PI3K3 Akt signaling. These experiments provide the first evidence that activation of Akt and ERK 1/2 are crucial events in leptin-mediated signal transduction leading to EC migration. Moreover, inhibition of leptin-directed migration by the PPAR␥-ligands TRO and CIG through inhibition of Akt underscores their potential in the prevention of diabetesassociated complications.