RhoA activation-mediated vascular permeability in capillary malformation-arteriovenous malformation syndrome: a hypothesis

•CM-AVM syndrome is a class of multi-focal capillary anomalies.•Most CM-AVMs arise due to loss of RASA1, resulting in constitutive RAS activation.•RASA1 forms a complex with RhoGAP, an inhibitor of RhoA signaling.•RAS activity is coupled with that of RhoA.•We hypothesize loss of RASA1 results in enhanced activation of RhoA signaling. Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is a class of capillary anomalies that are associated with arteriovenous malformations and arteriovenous fistulas, which carry a risk of hemorrhages. There are no broadly effective pharmacological therapies currently available. Most CM-AVMs are associated with a loss of RASA1, resulting in constitutive activation of RAS signaling. However, protein interaction analysis revealed that RASA1 forms a complex with Rho GTPase-activating protein (RhoGAP), a negative regulator of RhoA signaling. Herein, we propose that loss of RASA1 function results in constitutive activation of RhoA signaling in endothelial cells, resulting in enhanced vascular permeability. Therefore, strategies aimed at curtailing RhoA activity should be tested as an adjunctive therapeutic approach in cell culture studies and animal models of RASA1 deficiency.