The Phosphodiesterase 4 Inhibitor Roflumilast Protects Microvascular Endothelial Cells from Irradiation-Induced Dysfunctions
In endothelial cells, high-dose irradiation induces numerous dysfunctions including alteration in junctional proteins such as VE-Cadherin, apoptosis and enhanced adhesiveness linked to overexpression of adhesion molecules like Intercellular Adhesion Molecule 1 (ICAM-1). Such endothelial dysfunctions...
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2025-07-01
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| author | Nathalie Guitard Florent Raffin François-Xavier Boittin |
| author_facet | Nathalie Guitard Florent Raffin François-Xavier Boittin |
| author_sort | Nathalie Guitard |
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| description | In endothelial cells, high-dose irradiation induces numerous dysfunctions including alteration in junctional proteins such as VE-Cadherin, apoptosis and enhanced adhesiveness linked to overexpression of adhesion molecules like Intercellular Adhesion Molecule 1 (ICAM-1). Such endothelial dysfunctions can lead to altered tissue perfusion, development of tissue inflammation through increased endothelial permeability, and ultimately organ damage. As intracellular cyclic AMP (cAMP) levels are known to control intercellular junctions or apoptosis in the endothelium, we investigated here the effect of the Phosphodiesterase 4 inhibitor Roflumilast, a drug increasing cAMP levels, on irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). Using continuous impedance measurements in confluent endothelial cell monolayers, Roflumilast was found to rapidly reinforce the endothelial barrier and to prevent irradiation-induced barrier disruption. In accordance, irradiation-induced alteration in membrane VE-Cadherin-composed adherens junctions was prevented by Roflumilast treatment after irradiation, which was correlated with its protective effect of the actin cytoskeleton. Post-irradiation treatment with Roflumilast also protected HPMECs from irradiation-induced late apoptosis, but was without effect on irradiation-induced ICAM-1 overexpression. Overall, our results indicate that the beneficial effects of Roflumilast after irradiation are linked to the strengthening/protection of the endothelial barrier and reduced apoptosis, suggesting that this medicine may be useful for the treatment of endothelial damages after exposure to a high dose of radiation. |
| format | Article |
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| language | English |
| publishDate | 2025-07-01 |
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| spelling | doaj-art-e0fa98238ff848e981a85aa973ce64e22025-08-20T03:16:55ZengMDPI AGCells2073-44092025-07-011413101710.3390/cells14131017The Phosphodiesterase 4 Inhibitor Roflumilast Protects Microvascular Endothelial Cells from Irradiation-Induced DysfunctionsNathalie Guitard0Florent Raffin1François-Xavier Boittin2Unité de Radiobiologie, Département Effets Biologiques des Rayonnements, IRBA (Institut de Recherche Biomédicale des Armées), 91223 Brétigny-sur-Orge, FranceUnité Analyses Biologiques, Département des Plateformes, IRBA (Institut de Recherche Biomédicale des Armées), 91223 Brétigny-sur-Orge, FranceUnité de Radiobiologie, Département Effets Biologiques des Rayonnements, IRBA (Institut de Recherche Biomédicale des Armées), 91223 Brétigny-sur-Orge, FranceIn endothelial cells, high-dose irradiation induces numerous dysfunctions including alteration in junctional proteins such as VE-Cadherin, apoptosis and enhanced adhesiveness linked to overexpression of adhesion molecules like Intercellular Adhesion Molecule 1 (ICAM-1). Such endothelial dysfunctions can lead to altered tissue perfusion, development of tissue inflammation through increased endothelial permeability, and ultimately organ damage. As intracellular cyclic AMP (cAMP) levels are known to control intercellular junctions or apoptosis in the endothelium, we investigated here the effect of the Phosphodiesterase 4 inhibitor Roflumilast, a drug increasing cAMP levels, on irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). Using continuous impedance measurements in confluent endothelial cell monolayers, Roflumilast was found to rapidly reinforce the endothelial barrier and to prevent irradiation-induced barrier disruption. In accordance, irradiation-induced alteration in membrane VE-Cadherin-composed adherens junctions was prevented by Roflumilast treatment after irradiation, which was correlated with its protective effect of the actin cytoskeleton. Post-irradiation treatment with Roflumilast also protected HPMECs from irradiation-induced late apoptosis, but was without effect on irradiation-induced ICAM-1 overexpression. Overall, our results indicate that the beneficial effects of Roflumilast after irradiation are linked to the strengthening/protection of the endothelial barrier and reduced apoptosis, suggesting that this medicine may be useful for the treatment of endothelial damages after exposure to a high dose of radiation.https://www.mdpi.com/2073-4409/14/13/1017endothelial cellsVE-Cadherinactin cytoskeletonirradiationapoptosisICAM-1 |
| spellingShingle | Nathalie Guitard Florent Raffin François-Xavier Boittin The Phosphodiesterase 4 Inhibitor Roflumilast Protects Microvascular Endothelial Cells from Irradiation-Induced Dysfunctions Cells endothelial cells VE-Cadherin actin cytoskeleton irradiation apoptosis ICAM-1 |
| title | The Phosphodiesterase 4 Inhibitor Roflumilast Protects Microvascular Endothelial Cells from Irradiation-Induced Dysfunctions |
| title_full | The Phosphodiesterase 4 Inhibitor Roflumilast Protects Microvascular Endothelial Cells from Irradiation-Induced Dysfunctions |
| title_fullStr | The Phosphodiesterase 4 Inhibitor Roflumilast Protects Microvascular Endothelial Cells from Irradiation-Induced Dysfunctions |
| title_full_unstemmed | The Phosphodiesterase 4 Inhibitor Roflumilast Protects Microvascular Endothelial Cells from Irradiation-Induced Dysfunctions |
| title_short | The Phosphodiesterase 4 Inhibitor Roflumilast Protects Microvascular Endothelial Cells from Irradiation-Induced Dysfunctions |
| title_sort | phosphodiesterase 4 inhibitor roflumilast protects microvascular endothelial cells from irradiation induced dysfunctions |
| topic | endothelial cells VE-Cadherin actin cytoskeleton irradiation apoptosis ICAM-1 |
| url | https://www.mdpi.com/2073-4409/14/13/1017 |
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