Summary of the phenotype of mice with knockout of the components of endothelin system

Animal ModelSite (Cre)PhenotypeReferences
ECE-1−/−Whole bodyCraniofacial and cardiovascular defects; aganglionic megacolon and coat color spotting; embryonic lethalYanagisawa et al., 1998a
ECE-2−/−Whole bodyNo detectable abnormalitiesYanagisawa et al., 2000
ECE-1−/− ECE-2−/−Whole bodyMore severe cardiac abnormalities compared with ECE-1−/− miceYanagisawa et al., 2000
ET-1−/−Whole bodyAbnormalities in craniofacial and cardiovascular system, thyroid and thymus gland; neonatal lethalKurihara et al., 1994, 1995a.b
ET-1-/+Whole bodyMild blood pressure elevation; increased resting renal sympathetic nerve activityKurihara et al., 1994; Kuwaki et al., 1996; Ling et al., 1998; Morita et al., 1998; Kuwaki et al., 1999
ET-1 L/L or L/+Whole body20% and 65% ET-1 expression of a wild type mouse; dilated cardiomyopathy, elevated blood pressure, increased plasma volumeHathaway et al., 2015
Neuron ET-1−/−Neuron (synapsin I-Cre)Greater sensitivity to acute nociceptive stimuliHasue et al., 2005
Cardiomyocyte ET-1−/−Cardiomyocytes (alpha-myosin heavy chain -Cre)Shorter life span; age-associated reduction in cardiac functionZhao et al., 2006
Smooth muscle ET-1−/−Smooth muscle protein 22-CreNormal right ventricular systolic pressure basally; hypoxia leads to an attenuated increase in right ventricular systolic pressure compared with control miceKim et al., 2015
VEETKOEndothelium (Tie-2-Cre)Hypotensive to normotensive; ANGII hypertension is similar to controls but a reduction in cardiac hypertrophy and fibrosis; attenuation of oxidative stress, inflammation and injury following renal ischemia/reperfusion injury, hypoxia or high salt feedingKisanuki et al., 2010; Adiarto et al., 2012; Arfian et al., 2012; Heiden et al., 2014; Heimlich et al., 2015
Collecting duct ET-1−/−AQP2-CreElevated blood pressure; salt-sensitive hypertension; impaired ability to excrete waterAhn et al., 2004; Ge et al., 2005a, 2007, 2008b
ET-2−/−Whole bodyGrowth retardation; internal starvation; severe hypothermia; lung dysfunction; death at an early ageChang et al., 2013
inducible ET-2−/− knockoutWhole body (CAGGCre-ER)Reduced weight gain; reduced lipid deposition; mild hypothermiaChang et al., 2013
Intestinal epithelium ET-2−/−Villin-CreNormal growth and blood glucose levelChang et al., 2013
Neuron ET-2−/−Nestin-CreNormal core temperature; greater sensitivity to acute nociceptive stimuliChang et al., 2013
ET-3−/−Whole bodyAganglionic megacolon; coat color spotting; normotensive and normal baroreflex sensitivity; death at an early ageBaynash et al., 1994; Kuwaki et al., 2002
ls/lsWhole body, natural mutation in the ET-3 geneAganglionic megacolon; white spotting coatRice et al., 2000
ls/ls DβH-ET-3Naturally ET-3 deficient but ET-3 overexpressed in nerves (insertion with dopamine-β-hydroxylase promoter)Reduction in white spotting coat; rescued from megacolonRice et al., 2000
Piebald lethal s’/s’Natural deletion of the ETB gene from the whole bodyAganglionic megacolon; white spotting coatHosoda et al., 1994
ETA−/−Whole bodyCraniofacial and cardiovascular defects: lethal minutes after birthClouthier et al., 1998
Cardiomyocyte ETA−/−Cardiomyocytes (alpha-myosin heavy chain -Cre)Normal development and cardiovascular function; ANGII or isoproterenol-induced myocardial hypertrophy: protected from cold stressed-induced cardiac fibrosis and dysfunctionKedzierski et al., 2003; Zhang et al., 2012
Smooth muscle ETA−/−Smooth muscle protein 22-CreDefects of arterial network, mandibular and thymus structure; death at an early ageDonato et al., 2014
Collecting duct ETA−/−AQP2-CreNormotensive; impaired ability to excrete waterGe et al., 2005b
Whole nephron ETA−/−Inducible (Pax8-rtTA and LC-1)Normotensive; fluid retention during high salt intakeStuart et al., 2012; Stuart et al., 2013
ETB−/−Whole bodyAganglionic megacolon; white spotting coat; death at an early ageHosoda et al., 1994
ETB-/s’Whole body, 1 allele naturally mutatedSystemic ETB deficiency; reduced incidence of megacolon; 50% white coat spotting; increased blood pressure; normal cardiac sympathetic and vagal activity; reduced brain and lung ETAOhuchi et al., 1999; Davenport and Kuc 2004; Kuc et al., 2006
ETB−/−+ETB-DβHETB deficient except for nerves (insertion with dopamine-β-hydroxylase promoter)ETB expressed in nerves but absent elsewhere; white spotted coat; rescued from megacolon; elevated blood pressure; salt-sensitive blood pressure; endothelial dysfunctionMurakoshi et al., 2002; Quaschning et al., 2005
ECETB−/−Endothelium (Tie-2-Cre)Endothelial dysfunction; normotensive; red cell congestion of the intrahepatic branch of portal veinBagnall et al., 2006; Kelland et al., 2010b; Ling et al., 2012
Collecting duct ETB−/−AQP2-CreElevated blood pressure; increased ENaC activity; salt-sensitive hypertensionGe et al., 2006; Bugaj et al., 2012
Collecting duct ETA−/−/ETB−/−AQP2-CreElevated blood pressure; increased ENaC activity; salt-sensitive hypertensionGe et al., 2008a; Bugaj et al., 2012