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 G?q, the ?-subunit of the heterotrimeric Gq protein that activates phospholipase C?. 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 G?q (Aim 3). These studies will deepen our understanding of how G?q 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.

Public Health Relevance

Capillary malformations, one form of which is port-wine stain, are abnormal blood vessels in the dermis that associated with a rare neurologic disorder called Sturge-Weber syndrome wherein capillary malformations are also found on the surface of the brain and in the eye. A mutation has been found associated with both capillary malformation and Sturge- Weber syndrome, providing a clue to what might be causing abnormal blood vessels to form and grow in both conditions. Our lab is developing experimental models for capillary malformations so that we can elucidate the mechanisms driving the abnormal blood vessels and identify drugs that could potentially be used to prevent or minimize capillary malformations.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Charette, Marc F
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Boston Children's Hospital
United States
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Greene, Arin K; Goss, Jeremy A (2018) Vascular Anomalies: From a Clinicohistologic to a Genetic Framework. Plast Reconstr Surg 141:709e-717e
Couto, Javier A; Ayturk, Ugur M; Konczyk, Dennis J et al. (2017) A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth. Angiogenesis 20:303-306
Huang, Lan; Couto, Javier A; Pinto, Anna et al. (2017) Somatic GNAQ Mutation is Enriched in Brain Endothelial Cells in Sturge-Weber Syndrome. Pediatr Neurol 67:59-63
Couto, Javier A; Huang, August Y; Konczyk, Dennis J et al. (2017) Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation. Am J Hum Genet 100:546-554
Couto, Javier A; Konczyk, Dennis J; Vivero, Matthew P et al. (2017) Somatic PIK3CA mutations are present in multiple tissues of facial infiltrating lipomatosis. Pediatr Res 82:850-854
Ayturk, Ugur M; Couto, Javier A; Hann, Steven et al. (2016) Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma. Am J Hum Genet 98:789-95
Couto, Javier A; Huang, Lan; Vivero, Matthew P et al. (2016) Endothelial Cells from Capillary Malformations Are Enriched for Somatic GNAQ Mutations. Plast Reconstr Surg 137:77e-82e