Endothelial deletion of ADAM17 in mice results in defective remodeling of the semilunar valves and cardiac dysfunction in adults.
Global inactivation of the metalloproteinase ADAM17 during mouse development results in perinatal lethality and abnormalities of the heart, including late embryonic cardiomegaly and thickened semilunar and atrioventricular valves. These defects have been attributed in part to a lack of ADAM17-mediated processing of HB-EGF, as absence of soluble HB-EGF results in similar phenotypes. Because valvular mesenchymal cells are largely derived from cardiac endothelial cells, we generated mice with a floxed Adam17 allele and crossed these animals with Tie2-Cre transgenics to focus on the role of endothelial ADAM17 in valvulogenesis. We find that although hearts from late-stage embryos with ablation of endothelial ADAM17 appear normal, an increase in valve size and cell number is evident, but only in the semilunar cusps. Unlike Hbegf(-/-) valves, ADAM17-null semilunar valves do not differ from controls in acute cell proliferation at embryonic day 14.5 (E14.5), suggesting compensatory processing of HB-EGF. However, levels of the proteoglycan versican are significantly reduced in mutant hearts early in valve remodeling (E12.5). After birth, aortic valve cusps from mutants are not only hyperplastic but also show expansion of the glycosaminoglycan-rich component, with the majority of adults exhibiting aberrant compartmentalization of versican and increased deposition of collagen. The inability of mutant outflow valve precursors to transition into fully mature cusps is associated with decreased postnatal viability, progressive cardiomegaly, and systolic dysfunction. Together, our data indicate that ADAM17 is required in valvular endothelial cells for regulating cell content as well as extracellular matrix composition and organization in semilunar valve remodeling and homeostasis.
Department of Pathology, University of Washington, Seattle, WA 98104, USA. carolew2@u.washington.edu
Carole L
CL
Wilson
Peter J
PJ
Gough
Cindy A
CA
Chang
Christina K
CK
Chan
Jeremy M
JM
Frey
Yonggang
Y
Liu
Kathleen R
KR
Braun
Michael T
MT
Chin
Thomas N
TN
Wight
Elaine W
EW
Raines
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000375:Aging / Q000473:pathology*; D000818:Animals; D000831:Animals, Newborn; D001024:Aortic Valve Stenosis / Q000150:complications / Q000196:embryology / Q000473:pathology / Q000503:physiopathology; D017209:Apoptosis; D006332:Cardiomegaly / Q000150:complications / Q000196:embryology / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D003433:Crosses, Genetic; D004562:Electrocardiography; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006351:Heart Valves / Q000196:embryology / Q000473:pathology* / Q000503:physiopathology* / Q000648:ultrastructure; D066257:Heparin-binding EGF-like Growth Factor; D006820:Hyaluronic Acid / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D042787:Receptor, TIE-2 / Q000378:metabolism; D016019:Survival Analysis; D013599:Systole; D053675:Versicans / Q000378:metabolism
C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D053675:Versicans; D006820:Hyaluronic Acid; D003094:Collagen; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; C045073:Cre recombinase; D019426:Integrases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse