The role of laminin-1 in the modulation of radiation damage in endothelial cells and differentiation.
Microvascular dysfunction due to endothelial damage is often associated with the ionizing radiation used during cancer therapy. This radiation-induced capillary injury is a major factor in the inhibition of new vessel growth (angiogenesis) and in disease states such as radiation-induced pneumonitis and nephropathy. Many studies have examined the effects of radiation on endothelial cell function; however, little is known regarding the role the basement membrane plays in radiation-induced endothelial cell damage and angiogenesis. Therefore, we examined the effects of gamma radiation on aortic explants, and in vitro on three endothelial cell types (of artery, vein and capillary origin) irradiated with or without the basement membrane glycoprotein laminin-1. As expected, irradiation inhibited angiogenic sprouting of the aortic explants, endothelial cell proliferation, attachment, migration and differentiation in vitro in a dose-dependent manner. However, the effect of radiation on several of these processes in angiogenesis was reduced when the cells were irradiated on laminin-1. To further evaluate the effects of radiation on endothelial cells, we examined the expression of the vascular endothelial cell growth factor (VEGF) kinase domain region receptor in endothelial cells irradiated in the presence and absence of laminin-1. In endothelial cells irradiated on laminin-1, KDR expression increased 2.5-fold over control levels. Therefore, although radiation has a dose-dependent inhibitory effect on processes associated with angiogenesis in vitro, the presence of the basement membrane glycoprotein laminin-1 during irradiation decreases these effects.
Rose
R W
RW
The Cardeza Foundation for Hematological Research, Thomas Jefferson University, 1015 Walnut Street, Room 812, Philadelphia, Pennsylvania19107, USA.
Grant
D S
DS
O'Hara
M D
MD
Williamson
S K
SK
D000818:Animals; D001012:Aorta, Abdominal; D001013:Aorta, Thoracic; D002454:Cell Differentiation / Q000528:radiation effects; D002455:Cell Division / Q000528:radiation effects; D002478:Cells, Cultured; D003094:Collagen; D053938:DNA Fragmentation / Q000528:radiation effects; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology / Q000528:radiation effects*; D005720:Gamma Rays; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects; D006801:Humans; D007700:Kinetics; D007797:Laminin / Q000494:pharmacology / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000528:radiation effects*; D009924:Organ Culture Techniques; D011509:Proteoglycans; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D013997:Time Factors; D014471:Umbilical Veins
D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D017978:Receptors, Growth Factor; C059485:matrigel; D003094:Collagen; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor