Lipopolysaccharide-Induced Apoptosis of Endothelial Cells and Its Inhibition by Vascular Endothelial Growth Factor

Abstract

Endothelial injury is a major manifestation of septic shock induced by LPS. Recently, LPS was shown to induce apoptosis in different types of endothelial cells. In this study, we observed that pretreatment with vascular endothelial growth factor (VEGF), a known cell survival factor, blocked LPS-induced apoptosis in endothelial cells. We then further defined this LPS-induced apoptotic pathway and its inhibition by VEGF. We found that LPS treatment increased caspase-3 and caspase-1 activities and induced the cleavage of focal adhesion kinase. LPS also augmented expression of the pro-apoptotic protein Bax and the tumor suppressor gene p53. The pro-apoptotic Bax was found to translocate to the mitochondria from the cytosol following stimulation with LPS. Pretreatment of endothelial cells with VEGF inhibited the induction of both Bax and p53 as well as the activation of caspase-3. These data suggest that VEGF inhibits LPS-induced endothelial apoptosis by blocking pathways that lead to caspase activation.

Hyperoxic Ventilated Premature Baboons Have Increased p53, Oxidant DNA Damage and Decreased VEGF Expression

“…Although our data cannot identify the mesenchymal cells that express these factors, both p53 and p21 are increased in endothelial cells undergoing apoptosis in vitro (33,50). LPS-treated endothelial cells have increased p53 expression and become apoptotic, which can be prevented by pretreatment with VEGF (32).…”

“…In oxidant lung injury, p53 may inhibit cell proliferation by induction of p21 CIP1/WAF1 (hereafter p21) to allow repair of DNA damage (31). Expression of p53 is also characteristic of endothelial cells that are apoptotic (32,33). Although lung p53 is induced in adult rodent hyperoxic injury, it is not known whether p53 is induced in hyperoxic injury of developing lung.…”

Heat shock protein 70, heat shock protein 32, and vascular endothelial growth factor production and their effects on lipopolysaccharide-induced apoptosis in porcine aortic endothelial cells

“…Other molecules, such as VEGF, could possibly contribute to reduce LPS-induced apoptosis, as demonstrated by Munshi et al (2002). For this reason, we determined VEGF secretion and we observed an increase in VEGF production by LPS-stimulated PAEC.…”

“…It is well known that VEGF acts as a regulator of physiological and pathological angiogenesis as well as a permeability factor, effective in inducing vascular leakage (Ferrara et al 2003). Apart from these activities, VEGF acts as a survival signal, being effective in inhibiting the apoptosis process induced by a variety of stimuli such as hyperoxia (Alon et al 1995), growth-factor withdrawal, extracellular matrix disruption (Watanabe and Dvorak 1997), and lipopolysaccharide (LPS) (Munshi et al 2002).…”

The Tyrosine Kinase Pyk2 Mediates Lipopolysaccharide-Induced IL-8 Expression in Human Endothelial Cells

“…Endothelial cells express chemokines that initiate the activation and recruitment of circulating leukocytes at sites of tissue inflammation (3,4). The bacterial endotoxin, LPS, an essential component of the surface of Gram-negative bacteria (5), has potent proinflammatory properties by acting on many cell types including endothelial cells (3,6). High levels of LPS are a major cause of Gram-negative septic shock, in which LPS induces numerous changes, including up-regulation of adhesion molecules as well as procoagulant activity, enhanced endothelial permeability, and secretion of proinflammatory mediators by the endothelium (3,4,7).…”