Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases

Abstract

Exposure to ionizing radiation induces not only apoptosis but also senescence. While the role of endothelial cell apoptosis in mediating radiation-induced acute tissue injury has been extensively studied, little is known about the role of endothelial cell senescence in the pathogenesis of radiation-induced late effects. Senescent endothelial cells exhibit decreased production of nitric oxide and expression of thrombomodulin, increased expression of adhesion molecules, elevated production of reactive oxygen species and inflammatory cytokines and an inability to proliferate and form capillary-like structures in vitro. These findings suggest that endothelial cell senescence can lead to endothelial dysfunction by dysregulation of vasodilation and hemostasis, induction of oxidative stress and inflammation and inhibition of angiogenesis, which can potentially contribute to radiation-induced late effects such as cardiovascular diseases (CVDs). In this article, we discuss the mechanisms by which radiation induces endothelial cell senescence, the roles of endothelial cell senescence in radiation-induced CVDs and potential strategies to prevent, mitigate and treat radiation-induced CVDs by targeting senescent endothelial cells.

FIG. 1

Ionizing radiation induces endothelial cell apoptosis and senescence in a dose-dependent manner. Exposure of endothelial cells to a very high dose (>10 Gy) of ionizing radiation (IR) induces apoptosis via activation of the acidic sphingomyelinase (aSMase) that hydrolyzes sphingomyelin (SM) on the plasma membrane to generate ceramide and to induce Bax and Bak. However, exposure of endothelial cells to a moderate (>0.5 Gy) or high dose (<10 Gy) of radiation primarily induces senescence via multiple pathways, as shown. ALK5, TGF-β type 1 receptor kinase; ATM, ataxia-telangiectasia mutated protein kinase; CHK2, checkpoint kinase 2; DSBs, DNA double-strand breaks; IGF1R, insulin-like factor-1 receptor; mTOR, mechanistic target of rapamycin; NFκB, nuclear factor κB; p38, p38 mitogen-activated protein kinases; PI3K, phosphtidylinositol-3-kinase; ROS, reactive oxygen species; and TGF-β, tumor growth factor β.

FIG. 2

Role of endothelial cell in radiation-induced acute tissue injuries and late effects. Panel A: Role of endothelial cell apoptosis in acute radiation syndrome (ARS) in the hematopoietic system, gastrointestinal (GI) system, and central nerve system (CNS). Acidic sphingomyelinase knockout (aSMase KO), basic fibroblast growth factor (bFGF), sphingosine-1-phosphate (S1P), and antibodies against ceramide (ceramide ab) can inhibit radiation-induced apoptosis in endothelial cells (ECs) and reduce radiation-induced acute injuries to various tissues. Panel B: Hypothetical roles of endothelial cell senescence in radiation-induced late effects (RLEs). EPCs, endothelial progenitor cells; NO, nitric oxide; ROS, reactive oxygen species; TM, thrombomodulin; PAI-1, plasminogen activator inhibitor-1; and CVDs, cardiovascular diseases.

FIG. 3

Potential strategies to prevent, mitigate, and treat radiation-induced CVDs by targeting senescent endothelial cells. Antioxidants, inhibitors of insulin/insulin-like growth factor I receptor (IGF1R), phosphtidylinositol-3-kinase (PI3K), mechanistic target of rapamycin (mTOR), p38, NFκB and TGF-β type 1 receptor (ALK5), and the activators of sirtuin 1 (SIRT1) may be used to prevent radiation-induced CVDs by inhibiting the induction of endothelial cell (EC) senescence. Clearance of senescent cells with a senolytic drug that can selectively kill senescent cells including senescent endothelial cells has the potential to be developed as novel therapeutic strategy to mitigate and treat radiation-induced CVDs. Antioxidants and inhibitors of mTOR, p38, NFκB, and Janus kinase (JAK) may prevent, mitigate, and treat radiation-induced CVDs by scavenging senescent cell-produced reactive oxygen species (ROS) and inhibiting senescence-associated secretory phenotype (SASP), respectively.

FIG. 4

Role of cellular senescence in radiation-induced late effects (RLEs). Senescent cells may mediate RLEs in part via increased production of reactive oxygen species (ROS) and expression of senescence-associated secretory phenotype (SASP).