Decreased vascular lesion formation in mice with inducible endothelial-specific expression of protein kinase Akt

Abstract

To determine whether endothelial Akt could affect vascular lesion formation, mutant mice with a constitutively active Akt transgene, which could be inducibly targeted to the vascular endothelium using the tet-off system (EC-Akt Tg mice), were generated. After withdrawal of doxycycline, EC-Akt Tg mice demonstrated increased endothelial-specific Akt activity and NO production. After blood flow cessation caused by carotid artery ligation, neointimal formation was attenuated in induced EC-Akt Tg mice compared with noninduced EC-Akt Tg mice and control littermates. To determine the role of eNOS in mediating these effects, mice were treated with N ω -nitro-l-arginine methyl ester (l-NAME). Neointimal formation was attenuated to a lesser extent in induced EC-Akt Tg mice treated with l-NAME, suggesting that some of the vascular protective effects were NO independent. Indeed, endothelial activation of Akt resulted in less EC apoptosis in ligated arteries. Immunostaining demonstrated decreased inflammatory and proliferative changes in induced EC-Akt Tg mice after vascular injury. These findings indicate that endothelial activation of Akt suppresses lesion formation via increased NO production, preservation of functional endothelial layer, and suppression of inflammatory and proliferative changes in the vascular wall. These results suggest that enhancing endothelial Akt activity alone could have therapeutic benefits after vascular injury.

Platelet-derived ERp57 mediates platelet incorporation into a growing thrombus by regulation of the αIIbβ3 integrin

“…27,28 This injury is not expected to cause endothelial cell denudation. 27 The integrity of the endothelial cell layer was preserved after FeCl 3 injury in our model as shown by the staining pattern for platelet endothelial cell adhesion molecule-1/CD31, 22 a constitutively expressed endothelial cell adhesion molecule (supplemental Figure 1). Incorporation of ERp57-deficient platelets into the thrombus was substantially decreased ( Figure 2C), with the decrease being statistically significant over the 2-to 10-minute time interval ( Figure 2D).…”

“…The presence of endothelial cells at the site of vascular injury was determined as described elsewhere 22 with some modifications (legend of supplemental Figure 1; see the Blood Web site).…”

Endothelial NOS is required for SDF-1α/CXCR4-mediated peripheral endothelial adhesion of c-kit+ bone marrow stem cells

“…32 The amount of endothelial injury in the target organ and time course of local NO production after eNOS activation by Akt may play an important role for therapeutic stem cell treatment. 33 In human endothelial cells, the induction of eNOS by TNF-a has recently been described by De Palma et al 34 In contrast, a downregulation of eNOS was observed in association with high levels of TNF-a in patients with type 2 diabetes and microangiopathy. 35 Systemic L-NAME treatment and thereby …”

Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway

“…Overexpression of Akt1 in endothelial cells in the adult stage also induces pathological blood vessel formation reminiscent of tumor vasculature (Phung et al 2006). However, during blood flow cessation-induced neointimal formation, brief Akt activation in endothelial cells attenuates lesion formation (Mukai et al 2006). Presumably, transient activation of Akt1 in endothelial cells results in the maintenance of a functionally intact endothelial layer, and this pacifies the stimuli that promote smooth muscle growth in this model.…”