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JCI Insight ; 2(3): e90905, 2017 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-28194443

RESUMEN

In the central nervous system, endothelial cells (ECs) and pericytes (PCs) of blood vessel walls cooperatively form a physical and chemical barrier to maintain neural homeostasis. However, in diabetic retinopathy (DR), the loss of PCs from vessel walls is assumed to cause breakdown of the blood-retina barrier (BRB) and subsequent vision-threatening vascular dysfunctions. Nonetheless, the lack of adequate DR animal models has precluded disease understanding and drug discovery. Here, by using an anti-PDGFRß antibody, we show that transient inhibition of the PC recruitment to developing retinal vessels sustained EC-PC dissociations and BRB breakdown in adult mouse retinas, reproducing characteristic features of DR such as hyperpermeability, hypoperfusion, and neoangiogenesis. Notably, PC depletion directly induced inflammatory responses in ECs and perivascular infiltration of macrophages, whereby macrophage-derived VEGF and placental growth factor (PlGF) activated VEGFR1 in macrophages and VEGFR2 in ECs. Moreover, angiopoietin-2 (Angpt2) upregulation and Tie1 downregulation activated FOXO1 in PC-free ECs locally at the leaky aneurysms. This cycle of vessel damage was shut down by simultaneously blocking VEGF, PlGF, and Angpt2, thus restoring the BRB integrity. Together, our model provides new opportunities for identifying the sequential events triggered by PC deficiency, not only in DR, but also in various neurological disorders.


Asunto(s)
Anticuerpos/farmacología , Retinopatía Diabética/inmunología , Pericitos/citología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Angiopoyetina 2/metabolismo , Animales , Barrera Hematorretinal , Retinopatía Diabética/tratamiento farmacológico , Modelos Animales de Enfermedad , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Proteínas de la Membrana , Ratones , Pericitos/efectos de los fármacos , Pericitos/metabolismo , Proteínas/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismo
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