RESUMEN
Rho-associated protein kinase-2 (ROCK2) is a critical player in many cellular processes and was incriminated in cardiovascular and neurological disorders. Recent evidence has shown that non-selective pharmacological blockage of ROCKs ameliorates behavioral alterations in a mouse model of 16p11.2 haploinsufficiency. We had revealed that 16p11.2-deficient mice also display cerebrovascular abnormalities, including endothelial dysfunction. To investigate whether genetic blockage of ROCK2 also exerts beneficial effects on cognition and angiogenesis, we generated mice with both 16p11.2 and Rock2 haploinsufficiency (16p11.2df/+;Rock2+/-). We find that Rock2 heterozygosity on a 16p11.2df/+ background significantly improved recognition memory. Furthermore, brain endothelial cells from 16p11.2df/+;Rock2+/- mice display improved angiogenic capacity compared to cells from 16p11.2df/+ littermates. Overall, this study implicates Rock2 gene as a modulator of 16p11.2-associated alterations, highlighting its potential as a target for treatment of autism spectrum disorders.
Asunto(s)
Trastorno Autístico , Deleción Cromosómica , Trastornos de los Cromosomas , Cromosomas Humanos Par 16 , Modelos Animales de Enfermedad , Quinasas Asociadas a rho , Animales , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismo , Cromosomas Humanos Par 16/genética , Ratones , Trastorno Autístico/genética , Trastornos de los Cromosomas/genética , Heterocigoto , Reconocimiento en Psicología/fisiología , Células Endoteliales/metabolismo , Haploinsuficiencia , Masculino , Ratones Endogámicos C57BL , Anomalías Craneofaciales/genética , Discapacidad Intelectual/genéticaRESUMEN
Brain development and function are highly reliant on adequate establishment and maintenance of vascular networks. Early impairments in vascular health can impact brain maturation and energy metabolism, which may lead to neurodevelopmental anomalies. Our recent work not only provides novel insights into the development of cerebrovascular networks but also emphasizes the importance of their well-being for proper brain maturation. In particular, we have demonstrated that endothelial dysfunction in autism spectrum disorders (ASD) mouse models is causally related to altered behavior and brain metabolism. In the prenatal human brain, vascular cells change metabolic states in the second trimester. Such findings highlight the need to identify new cellular and molecular players in neurodevelopmental disorders, raising awareness about the importance of a healthy vasculature for brain development. It is thus essential to shift the mostly neuronal point of view in research on ASD and other neurodevelopmental disorders to also include vascular and metabolic features.