Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2

Tumor vessel dysfunction is a pivotal event in cancer progression. Using an in vivo neovascularization model, we identified G protein–coupled receptor kinase 2 (GRK2) as a key angiogenesis regulator. An impaired angiogenic response involving immature vessels was observed in mice hemizygous for Grk2 or in animals with endothelium-specific Grk2 silencing. ECs isolated from these animals displayed intrinsic alterations in migration, TGF-β signaling, and formation of tubular networks. Remarkably, an altered pattern of vessel growth and maturation was detected in postnatal retinas from endothelium-specific Grk2 knockout animals. Mouse embryos with systemic or endothelium-selective Grk2 ablation had marked vascular malformations involving impaired recruitment of mural cells. Moreover, decreased endothelial Grk2 dosage accelerated tumor growth in mice, along with reduced pericyte vessel coverage and enhanced macrophage infiltration, and this transformed environment promoted decreased GRK2 in ECs and human breast cancer vessels. Our study suggests that GRK2 downregulation is a relevant event in the tumoral angiogenic switch.Our laboratory is funded by grants from Ministerio de Educación y Ciencia (SAF2011-23800), Fundación Ramón Areces, The Cardiovascular Network (RECAVA) of Ministerio Sanidad y Consumo-Instituto Carlos III (RD06-0014/0037 and RD12/0042/0012), and Comunidad de Madrid (S-2010/BMD- 2332) to F. Mayor Jr. and Instituto Carlos III (PI11/00859), Fundación Ramón Areces, and Fundación Rodríguez Pascual to P. Penela. Marta Mendiola is supported by a postdoctoral research contract from Fondo de Investigación Sanitaria (“Sara Borrell” Programme), Instituto de Salud Carlos III

Temporal dysfunction in traumatic brain injury patients : primary or secondary impairment?

Adequate temporal abilities are required for most daily activities. Traumatic brain injury (TBI) patients often present with cognitive dysfunctions, but few studies have investigated temporal impairments associated with TBI. The aim of the present work is to review the existing literature on temporal abilities in TBI patients. Particular attention is given to the involvement of higher cognitive processes in temporal processing in order to determine if any temporal dysfunction observed in TBI patients is due to the disruption of an internal clock or to the dysfunction of general cognitive processes. The results showed that temporal dysfunctions in TBI patients are related to the deficits in cognitive functions involved in temporal processing rather than to a specific impairment of the internal clock. In fact, temporal dysfunctions are observed when the length of temporal intervals exceeds the working memory span or when the temporal tasks require high cognitive functions to be performed. The consistent higher temporal variability observed in TBI patients is a sign of impaired frontally mediated cognitive functions involved in time perception. -- Keywords : traumatic brain injury, time perception, time reproduction, time production, time discrimination, executive function