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(American Journal of Pathology. 2006;169:1484-1495.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060116

Influence of Endothelial Cells on Vascular Smooth Muscle Cells Phenotype after Irradiation

Implication in Radiation-Induced Vascular Damages

Fabien Milliat*{dagger}, Agnès François*{dagger}, Muriel Isoir*, Eric Deutsch{dagger}{ddagger}, Radia Tamarat*, Georges Tarlet*, Azeddine Atfi§, Pierre Validire, Jean Bourhis{dagger}{ddagger}, Jean-Christophe Sabourin|| and Marc Benderitter*{dagger}

From the Laboratory of Radiopathology,* Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses; Unité Propre de Recherche et de l’Enseignement Supérieur,{dagger} Equipe d’Accueil 2710 Laboratory of Radiosensitivity of Tumors and Normal Tissues and Department of Radiotherapy,{ddagger} Gustave Roussy Institute, Villejuif; INSERM U482,§ Saint-Antoine Hospital, Paris; Department of Pathology, Mutualiste Montsouris Institute, Paris; and Department of Pathology,|| Rouen University Hospital, Rouen, France

Damage to vessels is one of the most common effects of therapeutic irradiation on normal tissues. We undertook a study in patients treated with preoperative radiotherapy and demonstrated in vivo the importance of proliferation, migration, and fibrogenic phenotype of vascular smooth muscle cells (VSMCs) in radiation-induced vascular damage. These lesions may result from imbalance in the cross talk between endothelial cells (ECs) and VSMCs. Using co-culture models, we examined whether ECs influence proliferation, migration, and fibrogenic phenotype of VSMCs. In the presence of irradiated ECs, proliferation and migration of VSMCs were increased. Moreover, expressions of {alpha}-smooth muscle actin, connective tissue growth factor, plasminogen activator inhibitor type 1, heat shock protein 27, and collagen type III, alpha 1 were up-regulated in VSMCs exposed to irradiated ECs. Secretion of transforming growth factor (TGF)-ß1 was increased after irradiation of ECs, and irradiated ECs activated the Smad pathway in VSMCs by inducing Smad3/4 nuclear translocation and Smad-dependent promoter activation. Using small interferring RNA targeting Smad3 and a TGFß-RII neutralizing antibody, we demonstrate that a TGF-ß1/TGF-ß-RII/Smad3 pathway is involved in the fibrogenic phenotype of VSMCs induced by irradiated ECs. In conclusion, we show the importance of proliferation, migration, and fibrogenic phenotype of VSMCs in patients. Moreover, we demonstrate in vitro that ECs influence these fundamental mechanisms involved in radiation-induced vascular damages.




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F. Milliat, J.-C. Sabourin, G. Tarlet, V. Holler, E. Deutsch, V. Buard, R. Tamarat, A. Atfi, M. Benderitter, and A. Francois
Essential Role of Plasminogen Activator Inhibitor Type-1 in Radiation Enteropathy
Am. J. Pathol., March 1, 2008; 172(3): 691 - 701.
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