Acidification Prevents Endothelial Cell Apoptosis by Axl Activation

Abstract

Abstract-Prior studies have shown that acidification due to hypercarbia protects endothelial cells from serum deprivation-induced apoptosis. However, the mechanism(s) responsible for the antiapoptotic effect of acidification is still unclear. cDNA array screening was performed on human umbilical vein endothelial cells cultured in a bicarbonate medium equilibrated either with 5% CO 2 (pH 7.4) or with 20% CO 2 (pH 7.0). Tyrosine kinase receptor Axl expression was 3.3-fold higher after 6 hours at pH 7.0 compared with pH 7.4; this modulation was confirmed by reverse transcriptase-polymerase chain reaction (3.0Ϯ0.9-fold, PϽ0.03; nϭ3), Northern blot (3.6Ϯ0

Hypercapnic acidosis confers antioxidant and anti-apoptosis effects against ventilator-induced lung injury

“…21 Thus, our study demonstrated that hypercapnic acidosis may also affect the VILI by mediating the pathways of ASK1-JNK and p38 MAPK, apoptosis, and inflammatory cytokines in a rat model. 44 …”

Development of a Novel Immunoassay for the Assessment of Plasma Gas6 Concentrations and Their Variation with Hormonal Status

“…Indeed, the binding of Gas6 to Axl favors survival of human endothelial cells during acidification (22 ) and protects rat vascular smooth muscle cells from apoptosis (23 ). Moreover, mice deficient for Gas6 receptors present vessel wall abnormalities, including altered histology, increased apoptosis, and cellular degeneration (21 ).…”

Inhibition of vascular endothelial growth factor receptor 2–mediated endothelial cell activation by Axl tyrosine kinase receptor

“…The differences usually depend on the cell type studied and the concentration used. 4,5,[13][14][15][16][17][18][19][20] It induces migration of smooth muscle cells and inhibits neutrophil adhesion to ECs. 4,20 High concentrations of GAS6 (100-800 ng/mL) inhibit EC apoptosis.…”

“…[10][11][12] GAS6 shows the higher affinity for Axl, and its interaction generally triggers antiapoptotic signals, resulting in an augmented cell survival. In some cell types it regulates homotypic and heterotypic adhesion, 4,13 promotes proliferation, 5,14 survival, [15][16][17][18] and motility 19,20 and amplifies the activity of extracellular stimuli. 21,22 Vasculature may be a target of GAS6/Axl axis, being both molecules expressed by endothelial cells (ECs), 4,9 pericytes, 23 and smooth muscle cells.…”

“…24 GAS6/Axl interaction is involved in leukocyte transmigration through capillaries, 4,8 in neointima formation in injured vessels, 24 and in EC survival after tumor necrosis factor ␣ (TNF-␣) treatment or acidification. 16,18 Mice lacking the 3 tyrosine kinase receptors, which bind GAS6, show alteration in vasculature survival. 6 By activating specific and partially overlapping genetic programs, ECs play key roles in many processes, as regulation of vascular tone, lipid metabolism, hematopoiesis, inflammation, antigen recognition, thrombosis, hemostasis, and angiogenesis.…”