Vascular abnormalities in heart and brain are associated with cardiovascular and neurological symptoms in a novel mouse model for Williams syndrome

Abstract

AbstractWilliams syndrome is a developmental disorder caused by a microdeletion entailing loss of a single copy of 25-27 genes on chromosome 7q11.23. Patients with Williams syndrome suffer from cardiovascular and neuropsychological symptoms. So far, the structural abnormalities of the cardiovascular system in Williams syndrome have been attributed to the loss of a copy of the elastin (ELN) gene. In contrast, the neuropsychological consequences of Williams syndrome, including motor deficits, hypersociability and cognitive impairments, have been mainly attributed to altered expression of transcription factors like LIMK1, GTF2I and GTF2IRD1, while the potential secondary impact of altered cerebrovascular function has been largely ignored. To study the relation between the mutation underlying Williams syndrome and vascularization of not only the heart but also that of the brain, we generated a mouse model with a relatively long microdeletion, including theNcf1gene to reduce the confounding impact of hypertension. The affected mice had an elongated and tortuous aorta, but unlike inElnhaploinsufficient mice, there were no signs of structural cardiac hypertrophy. Our Williams syndrome mice had similar structural abnormalities in their coronary and brain vessels, showing disorganized extracellular matrices of the vessel walls. Moreover, our mouse model faithfully replicated both cardiovascular and neurological symptoms of Williams syndrome, highlighting that accurate non-invasive evaluation of complex vascular abnormalities is feasible. Altogether, we present evidence for vascular malformations that are similar in heart and brain, suggesting that cardiovascular and neurological symptoms can both by impacted by changes in the vascular structure in patients with Williams syndrome.