Capillary malformation: From somatic GNAQ mutations to disrupted endothelial biology

Project Abstract
Our studies are focused on capillary malformation (CM) (previously referred to as “port-wine stain”), the most
common type of vascular malformation. CM, excessive, enlarged capillary-like vessels just below the surface
of the skin, are sporadic congenital lesions that darken, form nodules, and cause soft-tissue and skeletal
overgrowth beneath the stain. Sturge-Weber syndrome (SWS) is a neurocutaneous disorder associated with
CMs of the face, leptomeninges, and the choroid of the eye; patients suffer from neurological defects and
glaucoma. Importantly, drug treatment for CMs does not exist and there is no cure.
The 2013 discovery of a somatic activating mutation in GNAQ (p.R183Q) in non-syndromic cutaneous CMs
and SWS CMs set the stage for molecular studies of this understudied vascular malformation. GNAQ encodes
Gαq, the α-subunit of the heterotrimeric Gq protein that activates phospholipase Cβ. We showed that the
GNAQ R183Q allele is enriched in the endothelial cell (EC) sorted from cutaneous CM and SWS brain
specimens. We have worked on creating cellular and mouse models to elucidate how the GNAQ mutation
affects EC function, how these alterations lead to CM, and how we can prevent the formation or growth of CM.
We show that human ECs with the R183Q mutation do not respond properly to laminar shear stress, fail to
form an endothelial barrier, and form enlarged CM-like vessels when implanted into mice. We implicate protein
kinase C (PKC) and angiopoietin-2 (ANGPT2) as potential targets to reverse the GNAQ R183Q-driven CM.
We are making strong progress towards an inducible, endothelial-specific knock-in of Gnaq R183Q in mice in
which we have found CM-like lesions upon tamoxifen-induced expression of the knocked-in mutant allele.
In this proposal we will identify the breadth of cell types that carry the somatic GNAQ R183Q allele and how
the mutation alters the transcriptional profile versus non-mutant cells of the same phenotype (Aim 1). We will
develop novel animal models in mice and zebrafish to elucidate the cellular steps leading to CM and will use
them as platforms for testing candidate drugs (Aim 2). We will deeply interrogate the role of (ANGPT2) as a
downstream functional mediator of constitutively active, mutant Gαq (Aim 3). These studies will deepen our
understanding of how Gαq activity participates in capillary morphogenesis, result in the first animal models for
CM/SWS, and provide a platform to test drugs that can prevent or regress CM. Discoveries about the
pathophysiology of CM will also help us understand the mechanisms that underlie additional vascular lesions
and improve our ability to identify new pathways for preventing vascular overgrowth (e.g., cancer) and
promoting vascular growth during tissue repair or engineering.

Grant Number: 5R01HL127030-08
NIH Institute/Center: NIH
Principal Investigator: Joyce Bischoff