Capillary malformations
Adrienne M. Hammill, Elisa Boscolo
Adrienne M. Hammill, Elisa Boscolo
Published April 15, 2024
Citation Information: J Clin Invest. 2024;134(8):e172842. https://doi.org/10.1172/JCI172842.
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Review Series

Capillary malformations

Abstract

Capillary malformation (CM), or port wine birthmark, is a cutaneous congenital vascular anomaly that occurs in 0.1%–2% of newborns. Patients with a CM localized on the forehead have an increased risk of developing a neurocutaneous disorder called encephalotrigeminal angiomatosis or Sturge-Weber syndrome (SWS), with complications including seizure, developmental delay, glaucoma, and vision loss. In 2013, a groundbreaking study revealed causative activating somatic mutations in the gene (GNAQ) encoding guanine nucleotide–binding protein Q subunit α (Gαq) in CM and SWS patient tissues. In this Review, we discuss the disease phenotype, the causative GNAQ mutations, and their cellular origin. We also present the endothelial Gαq-related signaling pathways, the current animal models to study CM and its complications, and future options for therapeutic treatment. Further work remains to fully elucidate the cellular and molecular mechanisms underlying the formation and maintenance of the abnormal vessels.

Authors

Adrienne M. Hammill, Elisa Boscolo

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Figure 2

Mutant GNAQ p.R183Q signaling in ECs.

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Mutant GNAQ p.R183Q signaling in ECs. Schematic of the molecular pathway...
Schematic of the molecular pathways involved in CM. The GNAQ activating mutation p.R183Q promotes disassembly of the heterotrimeric complex subunit αq from the β and γ subunits, impairing the hydrolysis of GTP to GDP. The Gαq bound to GTP promotes phospholipase C-β3 (PLCβ3) signaling, which catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol trisphosphate (IP3) and diacylglycerol (DAG). DAG leads to the activation of protein kinase C (PKC), which can in turn induce RAF (rapidly accelerated fibrosarcoma) kinase activation and MEK, which phosphorylates ERK1 and -2, promoting translocation into the nucleus and gene transcription. PKC can also induce NF-κB translocation into the nucleus, inducing ANGPT2 expression to promote proangiogenic signaling. The IP3 metabolite can activate its receptor, IP3R, on the endoplasmic reticulum, stimulating the release of calcium into the cytoplasm.