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1.
JCI Insight ; 2(11)2017 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-28570266

RESUMO

Microglia play a critical role in the development and homeostasis of the CNS. While mobilization of microglia is critical for a number of pathologies, understanding of the mechanisms of their migration in vivo is limited and often based on similarities to macrophages. Kindlin3 deficiency as well as Kindlin3 mutations of integrin-binding sites abolish both integrin inside-out and outside-in signaling in microglia, thereby resulting in severe deficiencies in cell adhesion, polarization, and migration in vitro, which are similar to the defects observed in macrophages. In contrast, while Kindlin3 mutations impaired macrophage mobilization in vivo, they had no effect either on the population of microglia in the CNS during development or on mobilization of microglia and subsequent microgliosis in a model of multiple sclerosis. At the same time, acute microglial response to laser-induced injury was impaired by the lack of Kindlin3-integrin interactions. Based on 2-photon imaging of microglia in the brain, Kindlin3 is required for elongation of microglial processes toward the injury site and formation of phagosomes in response to brain injury. Thus, while Kindlin3 deficiency in human subjects is not expected to diminish the presence of microglia within CNS, it might delay the recovery process after injury, thereby exacerbating its complications.

2.
Nat Commun ; 7: 10960, 2016 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-26971877

RESUMO

The signalling pathways operational in quiescent, post-development vasculature remain enigmatic. Here we show that unlike neovascularization, endothelial Akt signalling in established vasculature is crucial not for endothelial cell (EC) survival, but for sustained interactions with pericytes and vascular smooth muscle cells (VSMCs) regulating vascular stability and function. Inducible endothelial-specific Akt1 deletion in adult global Akt2KO mice triggers progressive VSMC apoptosis. In hearts, this causes a loss of arteries and arterioles and, despite a high capillary density, diminished vascular patency and severe cardiac dysfunction. Similarly, endothelial Akt deletion induces retinal VSMC loss and basement membrane deterioration resulting in vascular regression and retinal atrophy. Mechanistically, the Akt/mTOR axis controls endothelial Jagged1 expression and, thereby, Notch signalling regulating VSMC maintenance. Jagged1 peptide treatment of Akt1ΔEC;Akt2KO mice and Jagged1 re-expression in Akt-deficient endothelium restores VSMC coverage. Thus, sustained endothelial Akt1/2 signalling is critical in maintaining vascular stability and homeostasis, thereby preserving tissue and organ function.


Assuntos
Vasos Sanguíneos/metabolismo , Proteínas de Ligação ao Cálcio/genética , Células Endoteliais/metabolismo , Endotélio/metabolismo , Homeostase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas c-akt/genética , Angiografia , Animais , Materiais Biocompatíveis , Barreira Hematoencefálica/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Colágeno , Vasos Coronários/metabolismo , Combinação de Medicamentos , Ecocardiografia , Olho/irrigação sanguínea , Imunofluorescência , Regulação da Expressão Gênica , Coração , Células Endoteliais da Veia Umbilical Humana , Humanos , Immunoblotting , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína Jagged-1 , Laminina , Pulmão/irrigação sanguínea , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso , Pericitos , Proteoglicanas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Retina , Vasos Retinianos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Serrate-Jagged , Transdução de Sinais/genética , Microtomografia por Raio-X
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