Targetable cellular signaling events drive arterial rupture in knock-in mouse models of vascular Ehlers-Danlos Syndrome

Vascular Ehlers-Danlos Syndrome (vEDS) is an autosomal-dominant connective tissue disorder caused by heterozygous mutations in the COL3A1 gene. Currently, loss of structural integrity of the extracellular matrix is believed to drive the signs and symptoms of this condition, including spontaneous arterial dissection and/or rupture, the major cause of mortality. Using novel mouse models of vEDS that carry heterozygous Col3a1 glycine substitutions, we show that signaling abnormalities in the PLC/IP3/PKC/ERK pathway (Phospholipase C/Inositol 1,4,5-triphosphate/Protein Kinase C/Extracellular signal-regulated kinase) are major mediators of disease pathology and dissection. Treatment with pharmacologic agents that inhibit ERK1/2 and PKCβ activation prevent death due to spontaneous aortic rupture. Additionally, we find that pregnancy- or puberty-associated accentuation of vascular risk, also seen in vEDS patients, is rescued by attenuation of oxytocin or androgen signaling, respectively. Taken together, our results provide the first evidence that targetable signaling abnormalities contribute to the pathogenesis of vEDS, highlighting unanticipated therapeutic opportunities.