PAI-1-Dependent Endothelial Cell Death Determines Severity of Radiation-Induced Intestinal Injury

Abstract

Normal tissue toxicity still remains a dose-limiting factor in clinical radiation therapy. Recently, plasminogen activator inhibitor type 1 (SERPINE1/PAI-1) was reported as an essential mediator of late radiation-induced intestinal injury. However, it is not clear whether PAI-1 plays a role in acute radiation-induced intestinal damage and we hypothesized that PAI-1 may play a role in the endothelium radiosensitivity. In vivo, in a model of radiation enteropathy in PAI-1 −/− mice, apoptosis of radiosensitive compartments, epithelial and microvascular endothelium was quantified. In vitro, the role of PAI-1 in the radiation-induced endothelial cells (ECs) death was investigated. The level of apoptotic ECs is lower in PAI-1 −/− compared with Wt mice after irradiation. This is associated with a conserved microvascular density and consequently with a better mucosal integrity in PAI-1 −/− mice. In vitro, irradiation rapidly stimulates PAI-1 expression in ECs and radiation sensitivity is increased in ECs that stably overexpress PAI-1, whereas PAI-1 knockdown increases EC survival after irradiation. Moreover, ECs prepared from PAI-1 −/− mice are more resistant to radiation-induced cell death than Wt ECs and this is associated with activation of the Akt pathway. This study demonstrates that PAI-1 plays a key role in radiation-induced EC death in the intestine and suggests that this contributes strongly to the progression of radiation-induced intestinal injury.

Flagellin or Lipopolysaccharide Treatment Modified Macrophage Populations after Colorectal Radiation of Rats

“…Immunohistochemistry combined with flow cytometric analysis showed a major infiltration of macrophages into the colonic mucosa and submucosa 7 days after irradiation, particularly at 20 Gy. The dose-dependant microvasculature apoptosis induced by irradiation may contribute to alter the transendothelial migration and in fine the monocytes-macrophages recruitment notably at the high dose of 27 Gy (Abderrahmani et al, 2012). Immunophenotyping demonstrated that these macrophages expressed TLR4 and TLR5 and that these specific TLR4 1 and TLR5 1 macrophage subsets were most frequent after irradiation.…”

Notch signalling restricts inflammation and serpine1 expression in the dynamic endocardium of the regenerating zebrafish heart

“…Moreover, Serpine1 regulates endothelial cell proliferation (Ploplis et al, 2004), apoptosis (Balsara and Ploplis, 2008;Abderrahmani et al, 2012) and migration (Isogai et al, 2001) and is upregulated in the injured neonatal heart (Darehzereshki et al, 2015).…”

Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases

“…They acquire SASP by expressing increased levels of inflammatory cytokines and adhesion molecules (15, 18, 25, 26, 57, 77, 79). Radiation-induced senescent endothelial cells expressed decreased levels of thrombomodulin (80, 81) and increased levels of plasminogen activator inhibitor-1 (PAI-1) (82, 83). All these changes in senescent endothelial cells lead to endothelial dysfunction, which results in inhibition of angiogenesis, induction of oxidative stress and inflammation and dysregulation of vasodilation and hemostasis.…”