HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/H65    most recent 00866.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Barrick, C. J. Articles by Threadgill, D. W. PubMed PubMed Citation Articles by Barrick, C. J. Articles by Threadgill, D. W.

Reduced EGFR causes abnormal valvular differentiation leading to calcific aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice

Departments of ¹Genetics, ²Medicine, and ³Cell and Molecular Physiology, ⁴Curriculum in Toxicology, ⁵Carolina Cardiovascular Biology Center, ⁶Carolina Center for Genome Sciences and Center for Environmental Health and Susceptibility, University of North Carolina, Chapel Hill, North Carolina; ⁷Department of Medicine, Northwestern University, Chicago, Illinois; ⁸Department of Medicine, University of Washington, Seattle, Washington; ⁹Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky; and ¹⁰Department of Genetics, North Carolina State University, Raleigh, North Carolina

Submitted 7 August 2008 ; accepted in final form 12 May 2009

Epidermal growth factor receptor (EGFR) signaling contributes to aortic valve development in mice. Because developmental phenotypes in Egfr-null mice are dependent on genetic background, the hypomorphic Egfr^wa2 allele was made congenic on C57BL/6J (B6) and 129S1/SvImJ (129) backgrounds and used to identify the underlying cellular cause of EGFR-related aortic valve abnormalities. Egfr^wa2/wa2 mice on both genetic backgrounds develop aortic valve hyperplasia. Many B6-Egfr^wa2/wa2 mice die before weaning, and those surviving to 3 mo of age or older develop severe left ventricular hypertrophy and heart failure. The cardiac phenotype was accompanied by significantly thicker aortic cusps and larger transvalvular gradients in B6-Egfr^wa2/wa2 mice compared with heterozygous controls and age-matched Egfr^wa2 homozygous mice on either 129 or B6129F1 backgrounds. Histological analysis revealed cellular changes in B6-Egfr^wa2/wa2 aortic valves underlying elevated pressure gradients and progression to heart failure, including increased cellular proliferation, ectopic cartilage formation, extensive calcification, and inflammatory infiltrate, mimicking changes seen in human calcific aortic stenosis. Despite having congenitally enlarged valves, 129 and B6129F1-Egfr^wa2/wa2 mice have normal lifespans, absence of left ventricular hypertrophy, and normal systolic function. These results show the requirement of EGFR activity for normal valvulogenesis and demonstrate that dominantly acting genetic modifiers curtail pathological changes in congenitally deformed valves. These studies provide a novel model of aortic sclerosis and stenosis and suggest that long-term inhibition of EGFR signaling for cancer therapy may have unexpected consequences on aortic valves in susceptible individuals.

epidermal growth factor receptor aortic sclerosis; hypertrophy; aortic stenosis; valvulogenesis