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Dev Biol. 2019 Nov 1;455(1):73-84. doi: 10.1016/j.ydbio.2019.07.011. Epub 2019 Jul 15.

Loss of flow responsive Tie1 results in Impaired
Aortic valve remodeling.

Author information

1
Division of Pediatrics Cardiology, Vanderbilt University, Nashville, TN, USA.
2
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
3
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
4
Division of Cardiology, The Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
5
Division of Pediatrics Cardiology, Vanderbilt University, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA. Electronic address: scott.baldwin@vumc.org.

Abstract

The mechanisms regulating endothelial cell response to hemodynamic forces required for heart valve development, especially valve remodeling, remain elusive. Tie1, an endothelial specific receptor tyrosine kinase, is up-regulated by oscillating shear stress and is required for lymphatic valve development. In this study, we demonstrate that valvular endothelial Tie1 is differentially expressed in a dynamic pattern predicted by disturbed flow during valve remodeling. Following valvular endocardial specific deletion of Tie1 in mice, we observed enlarged aortic valve leaflets, decreased valve stiffness and valvular insufficiency. Valve abnormalities were only detected in late gestation and early postnatal mutant animals and worsened with age. The mutant mice developed perturbed extracellular matrix (ECM) deposition and remodeling characterized by increased glycosaminoglycan and decreased collagen content, as well as increased valve interstitial cell expression of Sox9, a transcription factor essential for normal ECM maturation during heart valve development. This study provides the first evidence that Tie1 is involved in modulation of late valve remodeling and suggests that an important Tie1-Sox9 signaling axis exists through which disturbed flows are converted by endocardial cells to paracrine Sox9 signals to modulate normal matrix remodeling of the aortic valve.

KEYWORDS:

Endocardium; Extracellular matrix; Hemodynamics; Semilunar valves; Sox9

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