Hemodynamic Flow-Induced Mechanotransduction Signaling Influences the Radiation Response of the Vascular Endothelium

Natarajan, Mohan; Aravindan, Natarajan; Sprague, Eugene A.; Mohan, Sumathy

doi:10.1667/rr14410.1

Cited by 12 publications

(7 citation statements)

References 95 publications

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“…It is considered important to perform studies on EC under physiological laminar flow conditions (40, 41). These experiments, especially at ion accelerators, require an open access to the cell layer and to be adjustable to beam exit window geometry, e.g., vertical or horizontal positioning of samples, maximum sample dimensions for homogenous dose distribution, or penetration depth of ion beams (32).…”

Section: Resultsmentioning

confidence: 99%

Measuring Leukocyte Adhesion to (Primary) Endothelial Cells after Photon and Charged Particle Exposure with a Dedicated Laminar Flow Chamber

et al. 2017

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The vascular endothelium interacts with all types of blood cells and is a key modulator of local and systemic inflammatory processes, for example, in the adhesion of blood leukocytes to endothelial cells (EC) and the following extravasation into the injured tissue. The endothelium is constantly exposed to mechanical forces caused by blood flow, and the resulting shear stress is essential for the maintenance of endothelial function. Changes in local hemodynamics are sensed by EC, leading to acute or persistent changes. Therefore, in vitro assessment of EC functionality should include shear stress as an essential parameter. Parallel-plate flow chambers with adjustable shear stress can be used to study EC properties. However, commercially available systems are not suitable for radiation experiments, especially with charged particles, which are increasingly used in radiotherapy of tumors. Therefore, research on charged-particle-induced vascular side effects is needed. In addition, α-particle emitters (e.g., radon) are used to treat inflammatory diseases at low doses. In the present study, we established a flow chamber system, applicable for the investigation of radiation induced changes in the adhesion of lymphocytes to EC as readout for the onset of an inflammatory reaction or the modification of a pre-existing inflammatory state. In this system, primary human EC are cultured under physiological laminar shear stress, subjected to a proinflammatory treatment and/or irradiation with X-rays or charged particles, followed by a coincubation with primary human lymphocytes (peripheral blood lymphocytes (PBL)). Analysis is performed by semiautomated quantification of fluorescent staining in microscopic pictures. First results obtained after irradiation with X-rays or helium ions indicate decreased adhesion of PBL to EC under laminar conditions for both radiation qualities, whereas adhesion of PBL under static conditions is not clearly affected by irradiation. Under static conditions, no radiation-induced changes in surface expression of adhesion molecules and activation of nuclear factor kappa B (NF-κB) signaling were observed after single cell-based high-throughput analysis. In subsequent studies, these investigations will be extended to laminar conditions.

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Section: Resultsmentioning

confidence: 99%

Measuring Leukocyte Adhesion to (Primary) Endothelial Cells after Photon and Charged Particle Exposure with a Dedicated Laminar Flow Chamber

et al. 2017

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“…As endothelial cells in vivo are exposed to shear stress associated with blood flow, we reasoned that studies on endothelial responses to radiation ought to employ models that closely approximate the in vivo situation. Elsewhere too, reports on radiation-induced endothelial responses have shown that endothelial cells under flow respond differently to radiation than statically cultured cells [55]. This is because endothelial cells isolated from mice and kept for several passages in culture have an altered phenotype [39,56].…”

Section: Discussionmentioning

confidence: 99%

LGM2605 Reduces Space Radiation-Induced NLRP3 Inflammasome Activation and Damage in In Vitro Lung Vascular Networks

Chatterjee

Pietrofesa

Park

et al. 2019

IJMS

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Updated measurements of charged particle fluxes during the transit from Earth to Mars as well as on site measurements by Curiosity of Martian surface radiation fluxes identified potential health hazards associated with radiation exposure for human space missions. Designing mitigation strategies of radiation risks to astronauts is critical. We investigated radiation-induced endothelial cell damage and its mitigation by LGM2605, a radioprotector with antioxidant and free radical scavenging properties. We used an in vitro model of lung vascular networks (flow-adapted endothelial cells; FAECs), exposed to gamma rays, low/higher linear energy transfer (LET) protons (3–4 or 8–10 keV/µm, respectively), and mixed field radiation sources (gamma and protons), given at mission-relevant doses (0.25 gray (Gy)–1 Gy). We evaluated endothelial inflammatory phenotype, NLRP3 inflammasome activation, and oxidative cell injury. LGM2605 (100 µM) was added 30 min post radiation exposure and gene expression changes evaluated 24 h later. Radiation induced a robust increase in mRNA levels of antioxidant enzymes post 0.25 Gy and 0.5 Gy gamma radiation, which was significantly decreased by LGM2605. Intercellular cell adhesion molecule-1 (ICAM-1) and NOD-like receptor protein 3 (NLRP3) induction by individual or mixed-field exposures were also significantly blunted by LGM2605. We conclude that LGM2605 is a likely candidate to reduce tissue damage from space-relevant radiation exposure.

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“…Radiation injury to vascular endothelium under varying hydrodynamic-flow shear stress' influence critical regulators of vascular function such as endothelial nitric oxide synthase (eNOS). Furthermore, eNOS protein expression is elevated in in vitro experiments of blood vascular endothelial cells exposed to ionizing radiation with and without shear, but under shear conditions, eNOS expression is much greater than without (Natarajan et al 2016). eNOSderived nitric oxide has also been shown to regulate in vitro blood vascular permeability through VE-Cadherin and Rho GTPase-dependent regulation of actin cytoskeletal arrangement (Di Lorenzo et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Impairment of lymphatic endothelial barrier function by X-ray irradiation

Narayanan

Ford

Zawieja

2019

International Journal of Radiation Biology

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Purpose: Although the microvascular system is a significant target for radiation-induced effects, the lymphatic response to radiation has not been extensively investigated. This is one of the first investigations characterizing the lymphatic endothelial response to ionizing radiation. Materials and Methods: Rat mesenteric lymphatic endothelial cells (RMLECs) were exposed to X-ray doses of 0, 0.5, 1, 1.5, and 2 Gy. RMLEC cellular response was assessed 24 and 72-h post-irradiation via measures of cellular morphometry and junctional adhesion markers. RMLEC functional response was characterized via permeability experiments. Results: Cell morphometry showed radiation sensitivity at all doses. Notably there was a loss of cell-to-cell adhesion with irradiated cells increasing in size and cellular roundness. This was coupled with decreased β-catenin and VE-cadherin intensity and altered F-actin anisotropy, leading to a loss of intercellular contact. RMLEC monolayers demonstrated increased permeability at all doses 24h post-irradiation and at 2-Gy 72h post-irradiation. Conclusions: In summary, lymphatics show radiation sensitivity in the context of these cell culture experiments. Our results may have functional implications of lymphatics in tissue, with endothelial barrier dysfunction due to loss of cell-cell adhesion leading to leaky vessels and lymphedema. These preliminary experiments will build the framework for future investigations towards lymphatic radiation exposure response.

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Hemodynamic Flow-Induced Mechanotransduction Signaling Influences the Radiation Response of the Vascular Endothelium

Cited by 12 publications

References 95 publications

Measuring Leukocyte Adhesion to (Primary) Endothelial Cells after Photon and Charged Particle Exposure with a Dedicated Laminar Flow Chamber

Measuring Leukocyte Adhesion to (Primary) Endothelial Cells after Photon and Charged Particle Exposure with a Dedicated Laminar Flow Chamber

LGM2605 Reduces Space Radiation-Induced NLRP3 Inflammasome Activation and Damage in In Vitro Lung Vascular Networks

Impairment of lymphatic endothelial barrier function by X-ray irradiation

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