Acidosis Inhibits Endothelial Cell Apoptosis and Function and Induces Basic Fibroblast Growth Factor and Vascular Endothelial Growth Factor Expression

Abstract

Endothelial cells are exposed to an acidotic environment in a variety of pathological and physiological conditions. However, the effect of acidosis on endothelial cell function is still largely unknown, and it was evaluated in the present study. Bovine aortic endothelial cells (BAECs) were grown in bicarbonate buffer equilibrated either with 20% CO(2) (pH 7.0, acidosis) or 5% CO(2) (pH 7.4, control). Acidosis inhibited BAEC proliferation in 10% FCS, whereas by day 7 in serum-free medium, cell number was 3-fold higher in acidotic cells than in control cells. Serum deprivation enhanced BAEC apoptosis, and apoptotic cell death was markedly inhibited by acidosis. Additionally, acidosis inhibited FCS-stimulated migration in a modified Boyden chamber assay and FCS-stimulated differentiation into capillary-like structures on reconstituted basement membrane proteins. Conditioned media from BAECs cultured for 48 hours either at pH 7.0 or pH 7.4 enhanced BAEC proliferation and migration at pH 7.4, and both effects were more marked with conditioned medium from BAECs grown in acidotic than in control conditions. Acidosis enhanced vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) mRNA expression as well as bFGF secretion, and a blocking bFGF antibody inhibited enhanced BAEC migration in response to conditioned medium from acidotic cells. These results show that acidosis protects endothelial cells from apoptosis and inhibits their proangiogenic behavior despite enhanced VEGF and bFGF mRNA expression and bFGF secretion.

Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis

“…The strong association of LDH with bFGF activated pathway, however, may be due to HIF-independent reasons. For example, acidification of the tumour environment by lactate may account for bFGF overexpression (D'Arcangelo et al, 2000). On the other hand, a direct effect of bFGF on LDH cellular levels has been recently shown by Riera et al (2002).…”

In vitro assessment of bone marrow endothelial colonies (CFU-En) in non-Hodgkin's lymphoma patients undergoing peripheral blood stem cell transplantation

“…[25][26][27] Based on these data it can be said that in remission phase of NHL patients perturbations and physiological stress such as those that may occur in the BM after chemotherapy do not prevent the growth of endothelial cells in contrast to what happened to the fibroblast component of the BM. The persistence of ECs may contribute to the bone marrow hematopoietic reconstitution by producing potent stimulating factors such as b-FGF, which, under acidosis conditions, has been shown to stimulate EC proliferation and protection from apoptosis, 28 or VEGF that can be produced in larger amounts by repopulating progenitors, which can ultimately stimulate (by a paracrine loop) the proliferation of both immature (angioblasts) and differentiated endothelial cells. 29,30 Furthermore, it must be said that some of these patients received radiotherapy, which can induce an upregulation of the E-9 protein (CD105) in human vascular endothelial cells.…”

Pyruvate improves redox status and decreases indicators of hepatic apoptosis during hemorrhagic shock in swine

“…However, the impact of these changes on apoptosis in vivo is unclear. In vitro studies of the relationship between acidosis and apoptosis provide conflicting results (9,10,37). Furthermore, the effects of other methods of systemic alkalinization were not evaluated because the use of bicarbonate or Carbicarb has not been shown to be beneficial in improving outcome during hemorrhagic shock (2,3).…”