Energy Deposition leads to Occurrence, Vascular Remodeling

Reference

Experimental Description

Result

Sridharan et al., 2020 

In vivo. In study B, male rats were exposed to oxygen ions (0.01-0.25 Gy). Heart tissue analysis was performed 6-7 and 12 months after radiation using histology and western blots.

Study B: 

At 12 months after ¹⁶O exposure, the tissue content of the 75 kDa collagen type III peptide increased 2.3-fold and 2-fold at 0.05 Gy and 0.25 Gy respectively.

Soucy et al., 2007 

In vivo. Sprague-Dawley rats were irradiated with ¹³⁷Cs gamma rays (0.5, 1.6, 5 Gy). Vascular stiffness was calculated using PWV with an ECG and doppler probe. 

At 0.5 and 1.6 Gy, PWV increased from 3.9 m/s (before irradiation) to 4.2 m/s. At 5 Gy PWV increased to 4.6 m/s. 

Grabham et al., 2011 

In vitro. 3D models of human vessels were created using human endothelial cells in gel matrix. Mature and developing vessel models were exposed to iron-ion (1 GeV/nucleon; LET 151 keV/um) and proton (1 GeV/nucleon; LET 0.22 keV/um) radiation at a 0.1-1 Gy/min dose rate or ¹³⁷Cs gamma radiation at 85 cGy/min dose rate.   

Vessel length as determined by length of capillary with lumen per cell was evaluated by DTAF staining for proteins and propidium iodide for nuclei.  

In mature vessels, iron-ion exposure reduced vessel length significant starting after 0.8 Gy with a 44% decrease in length after 1.6 Gy. Proton exposure produced no significant change, while gamma exposure required a dose of 6.4 Gy for significant vessel length breakdown.  

In developing vessels iron-ion exposure of 0.8 Gy decreased length by 50%, proton exposure of 0.4 Gy inhibited development and 0.8 Gy decreased length by 60%, while gamma exposure of 0.8 Gy inhibited vessel growth, and 6.4 Gy was required to reduce vessel length. 

Soucy et al., 2011 

In vivo. ⁵⁶Fe ions were used to irradiate rats at 0.5 or 1 Gy (0.5 Gy/min). PWV measured with Doppler probe and ECG and aortic wall thickness:lumen diameter ratio measured with histological analysis were used to determine vascular remodeling. 

After 0.5 Gy, there was no significant change in PWV, but at 1 Gy there was a significant 1.1-fold increase in PWV. No change in aortic wall thickness:lumen diameter was observed after either dose. 

Yu et al., 2011 

In vivo. ⁵⁶Fe ions were irradiated onto apoE-/- mice, and intima thickness of the carotid artery was measured using hematoxylin and eosin staining at 0, 2 and 5 Gy doses and a 13- and 40-weeks post-irradiation.  

13-weeks post irradiation, both 2 and 5 Gy doses showed a maximum 1.5-fold elevation in thickness compared to controls.  

40-weeks post irradiation there was no significant difference between the control, 2 Gy, and 5 Gy groups. 

Soucy et al., 2010 

In vivo. Rats were irradiated with 5 Gy ¹³⁷Cs gamma radiation and PWV, measured with Doppler probe and ECG was used as a measure of aortic stiffness and vascular remodeling. 

After 5 Gy, maximum PWV increased 1.2-fold compared to PWV pre-irradiation. 

Hamada et al., 2020 

In vivo. Male mice were irradiated by 5 Gy ¹³⁷Cs gamma rays (0.5 Gy/min) and compared to 0 Gy control. Vascular remodeling was measured through a Miles assay to show vascular permeability, vascular endothelial cadherin (VE-cadherin, a marker for adherens junctions) levels and number of endothelial detachments. 

Vascular permeability increased to a maximum of 16-fold as shown by staining intensity; VE-cadherin decreased to a maximum of 0.2-fold and percent of mice with total endothelial detachments increased from 0 to 90% at the maximum response. 

Hamada et al., 2021 

In vivo. Either acute or chronic doses of X-rays and ¹³⁷Cs gamma rays were given to B6J mice, all resulting in a total 5 Gy dose. X-rays were given as a single acute dose, 25 fractions of 0.2 Gy/fraction spread over 42 days or 100 fractions of 0.05 Gy/fraction spread over 153 days all given at 0.5 Gy/min. Gamma rays were given as a single acute dose at 0.5 Gy/min or chronically at <1.4 mGy/h for 153 days. Vascular remodeling was measured by IMT, collagen content (aniline blue staining), VE-cadherin levels and number of mice with detachments 6 months post-irradiation.  

IMT in the aorta increased about 2-fold after all X-ray treatments, but chronic gamma rays did not cause a change and acute gamma rays were not measured. Stained intensity to show collagen content increased about 1.5-fold for both the acute and 25 fractions X-ray regimens, but not in others. VE-cadherin decreased after acute gamma rays (0.2-fold) and all X-ray doses (0.2- to 0.3-fold). After acute gamma and X-rays and 25 fraction X-rays the percent of mice with a detachment went from 0 to a maximum of 100%. 

Hamada et al., 2022 

In vivo. Either acute or chronic doses of X-rays and ¹³⁷Cs gamma rays were given to B6J mice, all resulting in a total 5 Gy dose. X-rays were given as a single acute dose, 25 fractions of 0.2 Gy/fraction spread over 42 days or 100 fractions of 0.05 Gy/fraction spread over 153 days all given at 0.5 Gy/min. Gamma rays were given chronically at <1.4 mGy/h for 153 days. Vascular remodeling was measured by IMT, collagen content (aniline blue staining), VE-cadherin levels and number of mice with detachments 12 months post-irradiation. 

IMT in the aorta increased about 1.3-fold after X-rays in acute or 25 fraction regimens, but not after other regimens. Collagen content increased about 1.1-fold for all regimens except X-rays at 100 fractions. VE-cadherin decreased after all X-ray doses (maximum 0.5-fold). No mice were observed to have a detachment. 

Azimzadeh et al., 2015 

In vivo. 10-week-old male C57Bl/6 mice received cardiac irradiation at 8 or 16 Gy with X-rays. Serum oxLDL was measured using ELISA. 

oxLDL increased 1.2-fold after 8 Gy and 1.1-fold after 16 Gy compared to 0 Gy control. 

Shen et al., 2018 

In vivo. Male mice irradiated with 18 Gy X-rays had measurements of aortic thickness determined at various times using hematoxylin and eosin staining. The accumulation of collagen was measured using Sirius red staining. Endpoints were evaluated at 3-, 7-, 14-, 28- and 84-days post exposure and compared to a sham-irradiated control group.  

Sham-irradiated control:  

Thickness and collagen accumulation remained unchanged throughout the timepoints tested.  

18 Gy irradiated:  

Thickness and collagen accumulation were elevated above control at all time points tested. Thickness peaked 7-days post exposure with a 1.4-fold increase compared to controls.  

Collagen accumulation peaked at 14-days post exposure with a 1.4-fold increase above controls.   

Sarkozy et al., 2019 

In vivo. Rats were irradiated with 50 Gy electrons (5 Gy/min). Various markers of vascular remodeling, anterior and inferior wall thicknesses in systole (AWTs and IWTs) and diastole (AWTd and IWTd) were measured with an echocardiograph. Endpoints were evaluated at 1, 3 and 19-weeks post-irradiation. 

All three timepoints tested showed significant differences in cardiac structure measures between 50 Gy irradiated and 0 Gy control groups. By week 19, AWTs increased 1.3-fold, IWTs increased 1.1-fold, AWTd increased 1.5-fold and IWTd increased 1.2-fold. 

Russel et al., 2009  

Ex vivo. Recipient arteries from 147 patients receiving reconstructive surgery following treatment for head and neck cancer (H&N) or breast cancer (BC) were studied. H&N treatment group received 66 Gy (standard deviation 7 Gy) dose of radiation, while BC group received 49 Gy (standard deviation 3 Gy).  

Intimal-medial thickness in the form of intima-media ratio (IMR) was assessed through histology and proteoglycan and collagen content were scored. Analysis compared irradiated vessels, unirradiated vessels from the same patient as well as donor controls.  

In the H&N group the IMR was 1.5-fold greater without correction for the control artery.  

In the BC group the IMR increased 1.4-fold after correction for the control artery at a mean of 4 years following irradiation.  

There was an increase in the proteoglycan content of the intima of the irradiated IMA vessels, from 65% to 73%.  

Reference 

Experiment Description 

Result 

Sridharan et al., 2020 

In vivo. Male rats were exposed to oxygen ions and whole-body protons (0.5 Gy) to measure cardiac function and blood flow in study A. Measurements were taken at 3, 5, 9 and 12 months after radiation. Ultrasound, histology and Western blots were used as measurement methods. 

In study B, male rats were exposed to oxygen ions (0.01-0.25 Gy). Heart tissue analysis was performed 6-7 and 12 months after radiation using histology and western blots. 

Study A: 

At 3 and 5 months after proton and oxygen ion radiation, there was a significant decrease in left ventricular posterior wall thickness.  

12 months after oxygen ion exposures, velocity measures of pulsed wave Doppler of abdominal aorta increased.  

Cardiac volume increased at all time points in proton exposed rats, with a significance at 3 and 9 months. 

Collagen type III increased 2.4-fold after 12 months of 0.5 Gy protons radiation.  

Protein T lymphocyte markers CD2, CD4 and CD8 content in the rat hearts increased 6 months after a dose of ¹⁶O at 0.1 Gy.  

CD2, CD4 and CD8 increased 1.4-fold 12 months after ¹⁶O at 0.5 Gy. 

Soucy et al., 2007 

In vivo. Sprague-Dawley rat aorta was irradiated with 0.5, 1.6 and 5 Gy ¹³⁷Cs gamma rays. A measure of vascular stiffness and vascular remodeling was calculated using PWV and measurements taken with an ECG and doppler probe. 

At 1 day post irradiation in each group PWV significantly increased. At 1- and 2-weeks levels remained similar to the 1-day results, but slightly increased in the 500 cGy group and slightly decreased in the 50 and 160 cGy groups. 

Soucy et al., 2011 

In vivo. ⁵⁶Fe ions were used to irradiate rats (0.5 Gy/min). PWV measured with Doppler probe and ECG was used to determine vascular remodeling. 

At 4 months after irradiation with 1 Gy, PWV increased by ~0.5 m/s.  

At 8 months, PWV remained at a 0.5 m/s increase over control. 

Yu et al., 2011 

In vivo. 2 and 5 Gy ⁵⁶Fe ions were irradiated onto apoE-/- mice, and intima thickness of the carotid artery was measured using hematoxylin and eosin staining after 13 and 40 weeks. 

At both doses, after 13 weeks, intima thickness increased 1.4-fold. Intima thickness was the same as control after 40 weeks. 

Soucy et al., 2010 

In vivo. Rats were irradiated with 5 Gy ¹³⁷Cs gamma radiation and PWV, measured with Doppler probe and electrocardiogram (ECG) over 2 weeks, was used as a measure of aortic stiffness and vascular remodeling. 

PWV increased 1.1-fold (not significant) after 1 day, 1.2-fold after 1 week and 1.2-fold after 2 weeks. 

Hamada et al., 2020  

In vivo. Male mice were irradiated by 5 Gy ¹³⁷Cs gamma rays (0.5 Gy/min). Vascular remodeling was measured after 1, 3 and 6 months through a Miles assay to show vascular permeability, vascular endothelial cadherin (VE-cadherin, a marker for adherens junctions) levels and number of endothelial detachments. 

Vascular permeability increased 8-fold at 1 month, 16-fold at 3 months and 5-fold at 6 months shown by staining intensity. VE-cadherin decreased about 0.2-fold after 1, 3, and 6 months. Percent of mice with total endothelial detachments increased from 0 to 20% at 1 month, 34% at 3 months and 90% at 6 months post-irradiation. 

Shen et al., 2018 

In vivo. Male mice irradiated with 18 Gy X-rays had measurements of aortic thickness determined from 3 to 84 days post-irradiation using hematoxylin and eosin staining. The accumulation of collagen was measured using Sirius red staining from 3 to 84 days. 

Aortic thickness increased 1.1-fold after 3 days (ns), 1.4-fold after 7 days, 1.3-fold after 14 and 28 days and 1.2-fold (ns) after 84 days. Collagen increased 1.4-fold 14-, 28- and 84- days post-irradiation. 

Azimzadeh et al., 2015 

In vivo. 10-week-old male C57Bl/6 mice received cardiac irradiation at 8 or 16 Gy with X-rays. Serum oxLDL was measured using ELISA 16 weeks post-irradiation. 

After 16 weeks, oxLDL increased 1.2-fold after 8 Gy and 1.1-fold after 16 Gy compared to 0 Gy control.