Map2k6 is a potent genetic modifier of arterial rupture in vascular Ehlers-Danlos syndrome mice

• DOI: 10.1172/jci.insight.187315
• Publication Date: 2025-01-21T17:00:47Z
• Authors: Caitlin J. Bowen; Rebecca Sorber; Juan Francisco Ca...; Jefferson J. Doyle; Graham Rykiel; Zachary Burger; Xiaoyan Zhang; Wendy A. Espinoza...; Nicole Anderson; Simone Sabnis; Chiara Bellini; Elena Gallo MacFa...; Harry C. Dietz
• Keywords: Genetic disorder

Aortic dissection or rupture is a major cause of mortality in vascular Ehlers-Danlos Syndrome (vEDS), connective tissue disorder caused by heterozygous mutations the COL3A1 gene. C57BL6/J (BL6) mice carrying Col3a1 G938D/+ mutation recapitulate vEDS phenotype and die suddenly aortic rupture/dissection. However, 129S6/SvEvTac (129) expressing same show near-complete life-long protection from rupture. To identify genetic modifiers risk vEDS, we performed genome-wide genotyping intercrossed BL6/129 stratified survival identified significant protective locus encompassing variant Map2k6, encoding Mitogen-Activated Protein Kinase 6 (M2K6), p38-activating kinase. Genetic ablation Map2k6 rendered previously protected 129 susceptible to rupture, association with reduced protein phosphatase 1 activity increased PKC ERK phosphorylation. Accelerated treated pharmacological inhibitor p38 was rescued concomitant antagonism, supporting an opposing role for modification vEDS. These results suggest that pharmacologic strategies aimed at mimicking effect this natural pathway may improve prevention