Radiation-induced loss of endothelial alkaline phosphatase activity and development of myocardial degeneration. An ultrastructural study.

Background There is general agreement that radiation effects on capillary endothelial cells are a leading event in the pathogenesis of late effects of radiation in normal tissues. The mechanism of microvascular involvement however is unclear. In the myocardium, there is not only a decrease in capillary number, but a focal loss of endothelial alkaline phosphatase. The present study addresses the question of whether radiation-induced alkaline phosphatase loss is due to cell death or to modification of cell function and ultrastructure. Experimental design The time course of ultrastructural changes underlying endothelial alkaline phosphatase loss and development of myocardial degeneration was studied in two strains of rat, that differ in latent time of clinical radiation-induced cardiomyopathy. Results In both strains of rat, development of ultrastructural damage in cardiomyocytes was preceded by a focal loss of endothelial alkaline phosphatase reactivity. The absence of enzyme reaction product was neither due to endothelial cell loss, nor to a depletion in enzyme-bearing cytotoxic vesicles. The endothelial cell/pericyte relationship was also unchanged. Within enzyme-negative areas, there was an increased number of enlarged endothelial cells and of lymphocyte adherence to endothelial cells, which was then followed by endothelial cell rupture and extravasation of blood cells. In Wistar rats, enzyme loss started at 25 days after 20 Gy and reached its maximum extent by 90 days. In Sprague-Dawley rats, which show a significantly higher pre-irradiation enzyme reactivity, the onset of alkaline phosphatase loss and associated alterations was delayed by about 30 days and was significantly less extensive. Conclusions Radiation-induced endothelial alkaline phosphatase loss is unrelated to cell death in mitosis, but nonetheless it is relevant for the development of ultimate clinical heart failure.