Capillary malformation: From somatic GNAQ mutations and disrupted endothelial biology

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 DESCRIPTION (provided by applicant): Vascular malformations are defects in the architecture and function of blood vessels that can occur in arteries, veins, capillaries and lymphatic vessels. The malformations can be familial or sporadic, and are often associated with tissue overgrowth, deformity and infections in children, adolescents and adults. In this proposal, we will focus on capillary malformations (CM), which consist of excessive and abnormal capillary/venule-like vessels just below the surface of the skin. CMs are also referred to as port-wine stain or port-wine birthmarks. CM is a sporadic, non-familial congenital vascular malformation that is present at birth and progresses over a lifetime, causing significant morbidity for children. Sturge-Weber syndrome (SWS) is a rare neurological disorder that is strongly associated with CM. In SWS patients, CMs of variable size are located on one or both sides of the face, typically on the upper eyelid and forehead. In addition, excessive abnormal vessels are found on the surface of the brain and are thought to contribute to the neurologic deficits in children with SWS. A somatic, activating mutation in GNAQ (p.R183Q) has been reported in patients with SWS and CM, linking the vascular defect in these two disorders. GNAQ encodes Gαq, the alpha subunit of the heterotrimeric Gq protein that links G-protein coupled receptors to phospholipase Cβ. We confirmed the GNAQ (p.R183Q) mutation in CM specimens and then fractionated CM lesions into specific cell populations that were then genotyped for the GNAQ (p.R183Q) mutation. Our results, recently published, show that the GNAQ (p.R183Q) mutation is enriched in the endothelial cells of CM. With the identification of the molecular defect (Gαq) and the cellular context in which the defect resides (endothelial cells), we can now build a research program to investigate how CMs form, how to prevent CM and how to regress CM. These studies will be relevant for children with progressive, tissue-destroying CM and for children with SWS, as the abnormal vessels in the brain are likely disrupted by the same mechanisms. This research will have two tiers of impact. The first will be to decipher the underlying cellular and biochemical causes of CM, a relatively rare vascular malformation. The second will be much broader. The pathways and mechanisms discovered by our studies of CM may reveal unique and critical steps needed to assemble networks of human blood vessels. This will point to essential steps needed to build capillary networks for tissue regeneration and repair. Conversely, the lessons learned could be turned around and applied to prevention of pathological vessels in settings such as tumors, retinal diseases and rheumatoid arthritis. In summary, the study of CM could provide a well-spring of clues to advance our understanding of normal and pathologic vasculature.