RESUMEN
Coordinating angiogenesis with acquisition of tissue-specific properties in endothelial cells is essential for vascular function. In the retina, endothelial cells form a blood-retina barrier by virtue of tight junctions and low transcytosis. While the canonical Norrin/Fz4/Lrp5/6 pathway is essential for angiogenesis, vascular remodeling, and barrier maturation, how these diverse processes are coordinated remains poorly understood. Here we demonstrate that Apcdd1, a negative regulator of Wnt/ß-catenin signaling, is expressed in retinal endothelial cells during angiogenesis and barrier formation. Apcdd1-deficient mice exhibit a transient increase in vessel density at ages P10-P12 due to delayed vessel pruning. Moreover, Apcdd1 mutant endothelial cells precociously form the paracellular component of the barrier. Conversely, mice that overexpress Apcdd1 in retina endothelial cells have reduced vessel density but increased paracellular barrier permeability. Apcdd1 thus serves to precisely modulate Wnt/Norrin signaling activity in the retinal endothelium and coordinate the timing of both vascular pruning and barrier maturation.
Asunto(s)
Barrera Hematorretinal/fisiología , Péptidos y Proteínas de Señalización Intracelular/fisiología , Proteínas de la Membrana/fisiología , Vasos Retinianos/fisiología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Células Endoteliales/metabolismo , Células Endoteliales/fisiología , Endotelio/metabolismo , Endotelio/fisiología , Matriz Extracelular/fisiología , Matriz Extracelular/ultraestructura , Proteínas HMGB/metabolismo , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Ratones Transgénicos , Mutación/genética , Neuroglía/fisiología , Neuronas/fisiología , Pericitos/fisiología , Factores de Transcripción SOXF/metabolismo , Proteínas de Uniones Estrechas/metabolismoRESUMEN
The brain regulates blood flow to match energy demand to nutrient supply. In this issue of Neuron, using in vivo optical imaging and optogenetics, Hill et al. (2015) report that arteriolar smooth muscle cells are key players in regulating cerebral blood flow in the healthy state and contribute to the "no reflow" phenomenon after ischemic stroke.