An activating GNAQ R183Q mutation drives port wine birthmark lesion formation in a vascularized organ-on-chip microphysiological system
Abstract
Port-wine birthmark (PWB) is a progressive, congenital blood vessel disease that affects roughly one in 350 people and manifests as a light pink patch on the face or neck that can darken with age and develop soft tissue hypertrophy or nodularity. A portion of PWB patients have vascular lesions that are not superficial, affecting dentition, eyes, and/ or brain tissues and causing a variety of neurological and cognitive deficits called Sturge-Weber Syndrome (SWS). Most superficial PWB is resolved with pulsed-laser therapy during the first decade of life; deeper vascular lesions and some skin lesions, however, are difficult to treat and developing new therapeutic strategies has stalled over the last few decades. Several hurdles to therapeutic progress include poor understanding of disease biology and limited in vitro and in vivo models of PWB. Port-wine birthmarks are caused by endothelial somatic mutations within the Gnaq protein’s GTP hydrolysis site, which likely over-activates downstream growth and survival pathways of the endothelial cells containing a GNAQ mutation. We have used a multidisciplinary, translational approach to develop a microphysiological model of PWB lesions using our in vitro vascularized micro-organ (VMO) platform. Here we lay out our progress developing an autologous model of in vitro vasculogenesis for the study of PWB. We can recapitulate in this model using GNAQ-mutant vasculature the formation of dilated vascular lesions seen in patients. Through single cell transcriptome analysis of PWB patients and this model system, we additionally identify overexpression of BMP2 in PWB mutant EC as potential drivers of vascular lesion formation. Future experiments plan to leverage this novel mechanism for the discovery of effective therapeutics.