Hyperactive GNAQ in endothelial cells causes blood vessel malformation in developing mouse skin

Vascular anomalies are a group of congenital disorders characterized by structural abnormalities in the blood vessels. Over the past 20 years, genetic investigations have identified mosaic mutations in multiple genes in patients with vascular anomalies, including G protein alpha subunit q/11 encoding genes GNAQ/GNA11. Here, we report a tunable and reversible mouse tool for studying the frequent GNAQ mutant, GNAQ R183Q. We have generated a transgenic mouse line carrying the GNAQ R183Q under the control of the tet-responsive elements. The transgene expression level is tunable and can be induced at physiologically relevant ranges. We have shown that endothelial expression of GNAQ R183Q is sufficient to drive blood vessel malformation in developing mouse embryos. We have further identified multiple transcriptional changes caused by GNAQ R183Q in the skin by RNA-Seq. This work strengthens the causal link between GNA mutations and vascular anomalies, demonstrates that endothelial cell-specific expression of GNAQ R183Q is sufficient to cause vascular defects during development, and offers valuable insights into the mechanisms underlying GNA mutation-associated diseases.