# Radiation- and age-related vascular dysfunction as an early indicator of cardiovascular risk: a long-term study in the ApoE−/− mouse model of atherosclerosis

## TL;DR

This study shows that radiation and aging together cause vascular dysfunction in mice, especially in those prone to atherosclerosis, suggesting early blood pressure management is crucial for cancer survivors.

## Contribution

The study reveals combined age- and radiation-dependent vascular dysfunction in a mouse model of atherosclerosis, offering insights into early cardiovascular risk indicators.

## Key findings

- ApoE−/− mice showed greater radiation sensitivity and earlier vascular dysfunction compared to wild-type mice.
- Aging and radiation together caused reduced arterial diameters and slower vasodilation, indicating increased vascular resistance.
- Vasoconstrictive responses were enhanced in ApoE−/− mice and diminished at higher radiation doses.

## Abstract

Despite advances in radiotherapeutic techniques, radiation-induced cardiovascular diseases (CVD) remain a leading but often underrecognized cause of morbidity and mortality in cancer survivors. Radiation exposure can trigger a broad spectrum of cardiotoxic effects yet clinical awareness and strategies for managing these long-term complications remain limited. Among emerging indicators of vascular dysfunction, measures of vascular flexibility offer key biomarkers for assessing vascular compliance and cardiovascular risk.

The present study hence investigated age- and dose-dependent effects of local irradiation on vascular function of the murine Arteria saphena in C57BL/6 wild-type and atherosclerosis-prone apolipoprotein E-knockout (ApoE−/−) mice, a well established model for human CVD. Pathological effects of irradiation on vascular function of the A. saphena were assessed using in vivo Optical Coherence Tomography. Vascular flexibility in terms of arterial diameters and speed of diameter changes during vasoconstriction and vasodilation were recorded one day and 3, 6, 9, 12, or 18 months following irradiation with single doses of 2, 5, 8, 10, 16 Gy.

Baseline arterial diameters declined with age in both strains, with earlier onset in ApoE−/− mice. Significant interactions with radiation dose indicate greater radiation sensitivity in ApoE−/− mice and additive effects of radiation and aging in both strains. Vasoconstriction halved arterial diameters in wild-type and more so in ApoE−/− mice, reflecting an enhanced vasoconstrictive response that diminished after 16 Gy. Contractility was found to be age-dependent, peaking between 6 and 12 months post-irradiation, while time to half-maximal constriction remained unchanged across conditions. Maximal vasodilation ranged from 1.2 to 2 × baseline, initially higher in ApoE−/− mice but declining earlier with age than in wildtype mice. ApoE−/− mice exhibited more sustained vasodilation, which progressively slowed with age and higher radiation doses in both strains.

Both mouse strains exhibited marked age-related vascular changes, with ApoE−/− mice showing greater radiation sensitivity. The combined effects of aging and radiation were most prominent in reduced arterial diameters at baseline and after vasoconstriction, along with slower vasodilation reflecting elevated vascular resistance linked to hypertension. Early blood pressure management is therefore essential to reduce the risk of radiation-induced CVD.

The online version contains supplementary material available at 10.1186/s40959-025-00395-6.