Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development
Hiromi Yanagisawa, Robert E. Hammer, James A. Richardson, Noriaki Emoto, S. Clay Williams, Shin-ichi Takeda, David E. Clouthier, Masashi Yanagisawa
Hiromi Yanagisawa, Robert E. Hammer, James A. Richardson, Noriaki Emoto, S. Clay Williams, Shin-ichi Takeda, David E. Clouthier, Masashi Yanagisawa
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Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development

Abstract

Endothelin-converting enzyme-1 and -2 (ECE-1 and -2) are membrane-bound metalloproteases that can cleave biologically the inactive endothelin-1 (ET-1) precursor to form active ET-1 in vitro. We previously reported developmental defects in specific subsets of neural crest–derived tissues, including branchial arch–derived craniofacial structures, aortic arch arteries, and the cardiac outflow tract in ECE-1 knockout mice. To examine the role of ECE-2 in cardiovascular development, we have now generated a null mutation in ECE-2 by homologous recombination. ECE-2 null mice develop normally, are healthy into adulthood, are fertile in both sexes, and live a normal life span. However, when they are bred into an ECE-1–null background, defects in cardiac outflow structures become more severe than those in ECE-1 single knockout embryos. In addition, ECE-1–/–; ECE-2–/– double null embryos exhibited abnormal atrioventricular valve formation, a phenotype never seen in ECE-1 single knockout embryos. In the developing mouse heart, ECE-2 mRNA is expressed in the endocardial cushion mesenchyme from embyronic day (E) 12.5, in contrast to the endocardial expression of ECE-1. Levels of mature ET-1 and ET-2 in whole ECE-1–/–; ECE-2–/– embryos at E12.5 do not differ appreciably from those of ECE-1–/– embryos. The significant residual ET-1/ET-2 in the ECE-1–/–; ECE-2–/– embryos indicates that proteases distinct from ECE-1 and ECE-2 can carry out ET-1 activation in vivo.

Authors

Hiromi Yanagisawa, Robert E. Hammer, James A. Richardson, Noriaki Emoto, S. Clay Williams, Shin-ichi Takeda, David E. Clouthier, Masashi Yanagisawa

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Figure 7

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Schematic representation of the alignment between aortic (A) and pulmona...
Schematic representation of the alignment between aortic (A) and pulmonary (P) outflows in a frontal section (upper panel), alignment of A and P valves in a transverse section (middle panel), and alignment between A and P vessels and right (R) and left (L) ventricles (lower panel). (a) In wild-type embryos, aortic and pulmonary outflow tracts spiral around each other. The pulmonary valve locates rostrally (above the plane of the drawing; indicated by dotted lines) and anteriorly to the aortic valve so that two valves do not appear in a same plane. (b) In ECE-1–/– mutant embryos, the alignment between A and P outflows remains in a spiral position, whereas the aortic valve and outflow shift rostrally and to the right so that two valves appear in the same plane. The aorta often overrides the interventricular septum. (c) In ECE-1–/–; ECE-2–/– double mutant embryos, the aortic and pulmonary outflows run side by side in a parallel position, often showing double outlet right ventricle (DORV).