RESUMO
OBJECTIVES: The endothelium maintains vascular homeostasis through the release of endothelium-derived relaxing factors (EDRF) and endothelium-derived hyperpolarization (EDH). The balance in EDHâ:âEDRF is disturbed in cardiovascular disease and may also be susceptible to developmental conditioning through exposure to an adverse uterine environment to predispose to later risk of hypertension and vascular disease. METHODS: Developmentally conditioned changes in EDHâ:âEDRF signalling pathways were investigated in cremaster arterioles (18-32â µm diameter) and third-order mesenteric arteries of adult male mice offspring of dams fed either a fat-rich (high fat, HF, 45% energy from fat) or control (C, 10% energy from fat) diet. After weaning, offspring either continued on high fat or were placed on control diets to give four dietary groups (C/C, HF/C, C/HF, and HF/HF) and studied at 15 weeks of age. RESULTS: EDH via intermediate (IKCa) and small (SKca) conductance calcium-activated potassium channels contributed less than 10% to arteriolar acetylcholine-induced relaxation in in-situ conditioned HF/C offspring compared with â¼60% in C/C (Pâ<â0.01). The conditioned reduction in EDH signalling in HF/C offspring was reversed in offspring exposed to a high-fat diet both before and after weaning (HF/HF, 55%, Pâ<â0.01 vs. HF/C). EDH signalling was unaffected in arterioles from C/HF offspring. The changes in EDHâ:âEDRF were associated with altered endothelial cell expression and localization of IKCa channels. CONCLUSION: This is the first evidence that EDH-mediated microvascular relaxation is susceptible to an adverse developmental environment through down-regulation of the IKCa signalling pathway. Conditioned offspring exposed to a 'second hit' (HF/HF) exhibit adaptive vascular mechanisms to preserve dilator function.
Assuntos
Arteríolas/fisiopatologia , Fatores Biológicos/metabolismo , Dieta Hiperlipídica , Artérias Mesentéricas/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , RNA Mensageiro/metabolismo , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Acetilcolina/farmacologia , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/metabolismo , Dieta , Regulação para Baixo , Feminino , Hipertensão , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Camundongos , Óxido Nítrico , Óxido Nítrico Sintase Tipo III/genética , Norepinefrina/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
Eukaryotic initiation factor eIF4E and its phosphorylation play key roles in cell transformation and tumorigenesis. eIF4E is phosphorylated by the Mnks (MAP (mitogen-activated protein) kinase-interacting kinases). Rapamycin increases eIF4E phosphorylation in cancer cells, potentially limiting their anti-cancer effects. Here we show that the rapamycin-induced increase in eIF4E phosphorylation reflects increased activity of Mnk2 but not Mnk1. This activation requires a novel phosphorylation site in Mnk2a, Ser437. Our findings have potentially important implications for the use of rapamycin and its analogues in cancer therapy, suggesting that inhibitors of mTOR and Mnk (or Mnk2) may be more efficacious than rapalogs alone.