mTOR pathway effect on angiogenesis mechanisms in hyperglycemic conditions and diabetic placentas

Placenta has a complex vascular system and is very sensitive to alterations in maternal and fetal systems. Development and function of the vascular structures are affected from diabetic environment. Angiogenesis is regulated by several important molecules and signalling pathways. Although mTOR pathway is frequently studied for its roles in protein synthesis and translation mechanisms, angiogenesis regulatory effects has also been studied. However, the putative roles of mTOR pathway in diabetic angiogenesis mechanisms in human placenta haven't been studied yet. Therefore, in this study HUVECs are incubated at hyperglycemic conditions and mTOR pathway proteins and angiogenesis related proteins are examined. According to our results VEGF mRNA levels and soluble VEGF concentrations are increased in hyperglycemic conditions. VEGFR2 expression is both increased at mRNA and protein level. VEGFR1 level is increased only at mRNA level and increased HIF-1α expression is only detected at mRNA level. Akt phoshorylation is decreased, 4EBP1 phoshorylation is increased and p70S6K phoshorylation remained unaffected from hyperglycemic conditions. After mTOR inhibition, increased angiogenic responses are decreased. Besides hyperglycemia induced cellular migration and angiogenic network forming capacities are also decreased after mTOR pathway inhibition. It is detected that in diabetic female human term placentas, the pacental weight and mTOR, 4EBP1, VEGF and VEGFR2 expression levels are decreased but in male placentas it remained similiar between groups. Thus, for the first time with this study, the putative roles of mTOR signalling pathway in angiogenesis mechanisms in diabetic placentas and sex spesific changes have been reported.