T‐cadherin protects endothelial cells from oxidative stress‐induced apoptosis

ABSTRACT In vascular tissue, T‐cadherin (T‐cad) is up‐regulated in vivo under disease conditions associated with oxidative stress and concomitant cell migration, proliferation and apoptosis/survival. Using cultures of human umbilical vein endothelial cells (HUVEC), we examined whether there is a functional relationship between oxidative stress, T‐cad expression, and cell survival status. Culture of HUVEC under conditions of oxidative stress (e.g., serum deprivation, inclusion of 2H 2 O 2 ) resulted in increased T‐cad expression. Oxidative stress‐induced increases in T‐cad were inhibited by the free radical‐scavenging antioxidant, N‐acetylcysteine, and the flavin‐containing oxidase inhibitor, diphenyleneiodonium. Thus reactive oxygen species (ROS) contribute to stress‐induced elevation of T‐cad in HUVEC. Compared with control cells, HUVEC overexpressing T‐cad (T‐cad+‐HUVEC) had higher phosphorylation levels for phosphatidylinositol 3‐kinase (PI3K) target Akt and mTOR target p70 S6K (survival pathway regulators), but lower levels for p38MAPK (death pathway regulator). T‐cad+‐HUVEC exposed to stress (serum‐deprivation, TNF‐α, actinomycin D, staurosporine) exhibited reduced caspase activation together with increased cell survival. Protection against stress‐induced apoptosis in T‐cad+‐HUVEC was abrogated by either PI3K‐inhibitor wortmannin or mTOR‐inhibitor rapamycin. We conclude that T‐cad overexpression in HUVEC protects against stress‐induced apoptosis through activation of the PI3K/Akt/mTOR survival signal pathway and concomitant suppression of the p38 MAPK proapoptotic pathway. ROS‐induced changes in T‐cad expression may play an important role in controlling tissue cellularity during vascular remodeling.