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Cardiovascular Research 2006 71(4):754-763; doi:10.1016/j.cardiores.2006.06.002
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Copyright © 2006, European Society of Cardiology

Axl receptor activation mediates laminar shear stress anti-apoptotic effects in human endothelial cells

Daniela D'Arcangeloa,*, Valeria Ambrosinob, Maria Giannuzzoa, Carlo Gaetanoa and Maurizio C. Capogrossia

aLaboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Via dei Monti di Creta, 104 00167, Rome, Italy
bLaboratorio di Biologia Vascolare e Terapia Genica, Centro Cardiologico Fondazione "Monzino", Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy

* Corresponding author. Tel.: +39 06 6646 2428; fax: +39 06 6646 2430. Email address: d.darcangelo{at}idi.it

Objective: Laminar Shear Stress (SS) induces cytosolic acidification and protects endothelial cells (ECs) from apoptosis. Our prior studies showed that acidification protects ECs from serum deprivation-induced apoptosis by a mechanism directly involving Axl-receptor activation. Aim of the present study was to determine whether the anti-apoptotic action of SS involves acidification-dependent Axl activation.

Methods and results Axl mRNA and protein levels were significantly higher (5 and 8 fold, respectively) in ECs exposed to SS (12 dyne/cm2), compared to static culture (ST). This effect was dependent on the presence of bicarbonate ion and blocked by the anion exchangers inhibitors, DIDS and SITS. Moreover, DIDS markedly inhibited the anti-apoptotic action of SS. Notably, after 5 min of SS exposure, Axl-receptor was tyrosine-phosphorylated. The over-expression in human ECs of an Axl-receptor soluble form completely reverted the anti-apoptotic SS effect. Since laminar SS exerts its effects through the activation of integrin-dependent pathways, we examined whether Axl might be associated with the {alpha}vβ3 integrin complex known to be activated by SS. Co-immunoprecipitation experiments indicate that 5 min of ECs exposure to SS induced Axl-receptor/β3-integrin complex formation, suggesting their functional association.

Conclusions: These results indicate that Axl receptor activation modulates laminar SS anti-apoptotic effects possibly through its association with specific integrin-complexes.

KEYWORDS Acidification; Apoptosis; Axl tyrosine kinase receptor; Endothelial cells; Integrins; Mechanotransduction; Shear stress

Time for primary review 22 days


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