An Inducible Cre Mouse with Preferential Activity in Vascular Smooth Muscle Evades a Previously Lethal Intestinal Phenotype

Warthi, G. D.; Faulkner, J. L.; Doja, J.; Ghanam, A. R.; Gao, P.; Yang, A. C.; Slivano, O. J.; Barris, C. T.; Kress, T. C.; Zawieja, S. D.; Griffin, S. H.; Xie, X.; Ashworth, A.; Christie, C. K.; Bryant, W. B.; Kumar, A.; Davis, M. J.; Long, X.; Gan, L.; Belin de Chantemele, E. J.; Lyu, Q.; Miano, J. M.

doi:10.1101/2022.02.03.479061

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bioRxiv · 10.1101/2022.02.03.479061

An Inducible Cre Mouse with Preferential Activity in Vascular Smooth Muscle Evades a Previously Lethal Intestinal Phenotype

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Abstract

All smooth muscle cell (SMC) restricted Cre mice recombine floxed alleles in vascular and visceral SMCs. We generated a new tamoxifen-inducible CreERT2 mouse, Itga8-CreERT2, and compared its activity to the widely used Myh11-CreERT2 mouse. Both CreERT2 mice showed similar activity in vascular SMCs; however, Itga8-CreERT2 displayed limited activity in visceral SMC-containing tissues (e.g., intestine). Myh11-CreERT2 (but not Itga8-CreERT2) mice displayed high levels of CreERT2 protein, tamoxifen-independent activity, and an altered transcriptome. Whereas Myh11-CreERT2-mediated knockout of Srf resulted in a lethal intestinal phenotype, loss of Srf with Itga8-CreERT2 (SrfItga8) revealed viable mice with attenuated vascular SMC contractile gene expression, but no evidence of intestinal pathology. Male and female SrfItga8 mice presented with vascular contractile incompetence; however, only male SrfItga8 mice showed systemic changes in blood pressure. These results establish the Itga8-CreERT2 mouse as an alternative to existing SMC Cre strains, including Myh11-CreERT2, where SMC gene loss results in visceral myopathies that obfuscate accurate phenotyping in vascular SMCs.

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Warthi, G. D., Faulkner, J. L., Doja, J., Ghanam, A. R., Gao, P., Yang, A. C., Slivano, O. J., Barris, C. T., Kress, T. C., Zawieja, S. D., Griffin, S. H., Xie, X., Ashworth, A., Christie, C. K., Bryant, W. B., Kumar, A., Davis, M. J., Long, X., Gan, L., Belin de Chantemele, E. J., Lyu, Q., Miano, J. M.. 2022-02-04. An Inducible Cre Mouse with Preferential Activity in Vascular Smooth Muscle Evades a Previously Lethal Intestinal Phenotype. https://doi.org/10.1101/2022.02.03.479061

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