RESUMEN
The growth of hierarchical blood vessel networks occurs by angiogenesis. During this process, new vessel growth is accompanied by the removal of redundant vessel segments by selective vessel regression ('pruning') and a reduction in endothelial cell (EC) density in order to establish an efficient, hierarchical network. EC apoptosis has long been recognised for its association with angiogenesis, but its contribution to this process has remained unclear. We generated mice in which EC apoptosis was blocked by tissue-specific deletion of the apoptosis effector proteins BAK and BAX. Using the retina as a model, we found that apoptosis made a minor contribution to the efficiency of capillary regression around arteries where apoptosis was most concentrated, but was otherwise dispensable for vessel pruning. Instead, apoptosis was necessary for the removal of non-perfused vessel segments and the reduction in EC density that occurs during vessel maturation. In the absence of apoptosis, increased EC density resulted in an increase in the diameter of capillaries, but not arteries or veins. Our findings show that apoptosis does not influence the number of vessels generated during angiogenesis. Rather it removes non-perfused vessel segments and regulates EC number during vessel maturation, which has vessel-specific consequences for vessel diameter.
Asunto(s)
Apoptosis/fisiología , Endotelio Vascular/citología , Animales , Apoptosis/genética , Células Endoteliales/citología , Células Endoteliales/metabolismo , Masculino , Ratones , Neovascularización Patológica/metabolismo , Neovascularización Patológica/fisiopatología , Retina/citología , Retina/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Polycystic kidney disease (PKD) is a common cause of renal failure with few effective treatments. INPP5E is an inositol polyphosphate 5-phosphatase that dephosphorylates phosphoinositide 3-kinase (PI3K)-generated PI(3,4,5)P3 and is mutated in ciliopathy syndromes. Germline Inpp5e deletion is embryonically lethal, attributed to cilia stability defects, and is associated with polycystic kidneys. However, the molecular mechanisms responsible for PKD development upon Inpp5e loss remain unknown. Here, we show conditional inactivation of Inpp5e in mouse kidney epithelium results in severe PKD and renal failure, associated with a partial reduction in cilia number and hyperactivation of PI3K/Akt and downstream mammalian target of rapamycin complex 1 (mTORC1) signaling. Treatment with an mTORC1 inhibitor improved kidney morphology and function, but did not affect cilia number or length. Therefore, we identify Inpp5e as an essential inhibitor of the PI3K/Akt/mTORC1 signaling axis in renal epithelial cells, and demonstrate a critical role for Inpp5e-dependent mTORC1 regulation in PKD suppression.
Asunto(s)
Riñón/metabolismo , Complejos Multiproteicos/genética , Monoéster Fosfórico Hidrolasas/genética , Enfermedades Renales Poliquísticas/genética , Serina-Treonina Quinasas TOR/genética , Animales , Ciliopatías/tratamiento farmacológico , Ciliopatías/genética , Ciliopatías/patología , Modelos Animales de Enfermedad , Elafina/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Mutación de Línea Germinal , Humanos , Riñón/efectos de los fármacos , Riñón/patología , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Complejos Multiproteicos/antagonistas & inhibidores , Monoéster Fosfórico Hidrolasas/antagonistas & inhibidores , Enfermedades Renales Poliquísticas/tratamiento farmacológico , Enfermedades Renales Poliquísticas/patología , Proteínas Proto-Oncogénicas c-akt/genética , Eliminación de Secuencia , Transducción de Señal/efectos de los fármacos , Sirolimus/administración & dosificación , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
BACKGROUND AND PURPOSE: Improvements of language production in aphasic patients have been reported following repeated 1-Hz transcranial magnetic stimulation over the nondamaged right hemisphere. Most studies examined aphasic patients in the chronic phase. The effect of transcranial magnetic stimulation application in acute or subacute patients has not been systematically studied. We aimed to evaluate whether continuous theta burst stimulation, an inhibitory protocol with a shorter application time than the common 1-Hz protocol, is able to improve naming performance in aphasic patients in different poststroke phases. METHODS: Eighteen right-handed aphasic patients performed a picture naming task and a language independent alertness test before and after the application of theta burst stimulation over the intact right Broca's homologue localized by the 10-20 electroencephalogram system in a randomized, sham-controlled, crossover trial. RESULTS: We found that naming performance was significantly better, and naming latency was significantly shorter, after theta burst stimulation than after the sham intervention. Patients who responded best were in the subacute phase after stroke. CONCLUSIONS: This setting with the short theta burst stimulation application time and the simple stimulation localization procedure is suitable for clinical purposes.