Pathological effects of ionizing radiation: endothelial activation and dysfunction

Abstract

The endothelium, a tissue that forms a single layer of cells lining various organs and cavities of the body, especially the heart and blood as well as lymphatic vessels, plays a complex role in vascular biology. It contributes to key aspects of vascular homeostasis and is also involved in pathophysiological processes, such as thrombosis, inflammation, and hypertension. Epidemiological data show that high doses of ionizing radiation lead to cardiovascular disease over time. The aim of this review is to summarize the current knowledge on endothelial cell activation and dysfunction after ionizing radiation exposure as a central feature preceding the development of cardiovascular diseases.

Keywords: Endothelial cell retraction; Mitochondrial dysfunction; Premature senescence; Procoagulation; Prothrombosis; Vascular tone.

Fig. 1

Radiation-induced sterile inflammation in endothelial cells. Ionizing radiation exposure activates redox-sensitive transcription factor NF-κB via DSB and ATM signaling, induces oxidative stress, and triggers the release of DAMPs. The resulting inflammation leads to the production and secretion of pro-inflammatory cytokines as well as to the expression of a modified repertoire of adhesion molecules by irradiated endothelial cells

Fig. 2

Irradiation-induced deterioration of the vascular tone. Ionizing radiation exposure induces oxidative stress and DNA damage in endothelial cells (left), leading to decreased NO levels and altered production and/or secretion of vasoactive compounds resulting in an initial vasodilation followed by vasoconstriction. In addition, VSMC irradiation induces oxidative stress and DNA damage, resulting in an initial reduction of cellular viability and proliferation as well as vasodilation (right). In the long run, oxidative stress results in Ca²⁺ release from intracellular stores and increased VSMC proliferation, supporting vasoconstriction

Fig. 3

Irradiation-induced procoagulatory and prothrombotic state in endothelial cells. Endothelial irradiation results in a decreased production of anticoagulants prostacyclin and NO, resulting in a procoagulatory state. In addition, endothelial cell activation and general vascular damage result in elevated secretion of prothrombotic proteins (e.g., vWF) and a reduced fibrinolytic activity producing a prothrombotic state

Fig. 4

Irradiation-induced retraction and death of endothelial cells. Ionizing radiation exposure is able to decrease PECAM-1 expression, redistribute VE-cadherin, and produce actin stress fibers leading to endothelial retraction. Depending on the radiation dose, radiation quality, and inherent radiation sensitivity, ionizing radiation can activate the caspase pathway by ceramide formation and persistent p53 signaling, causing endothelial cell death. As a consequence of endothelial retraction and cell death, the physiological endothelial barrier is compromised

Fig. 5

Ionizing radiation can induce both endothelial cell activation and dysfunction. The resulting vasoconstrictive, pro-inflammatory, procoagulatory, prothrombotic, and prohypertrophic environment can initiate and/or trigger the progression of several pathological cardiovascular conditions, together with other vascular risk factors (e.g., dyslipidemia and hypertension)