TABLE 4.
Summary of the phenotype of mice with knockout of the components of endothelin system
| Animal Model |
Site (Cre) |
Phenotype |
References |
|---|---|---|---|
| ECE | |||
| ECE-1−/− | Whole body | Craniofacial and cardiovascular defects; aganglionic megacolon and coat color spotting; embryonic lethal | Yanagisawa et al., 1998a |
| ECE-2−/− | Whole body | No detectable abnormalities | Yanagisawa et al., 2000 |
| ECE-1−/− ECE-2−/− | Whole body | More severe cardiac abnormalities compared with ECE-1−/− mice | Yanagisawa et al., 2000 |
| ET-1 | |||
| ET-1−/− | Whole body | Abnormalities in craniofacial and cardiovascular system, thyroid and thymus gland; neonatal lethal | Kurihara et al., 1994, 1995a.b |
| ET-1-/+ | Whole body | Mild blood pressure elevation; increased resting renal sympathetic nerve activity | Kurihara 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 body | 20% and 65% ET-1 expression of a wild type mouse; dilated cardiomyopathy, elevated blood pressure, increased plasma volume | Hathaway et al., 2015 |
| Neuron ET-1−/− | Neuron (synapsin I-Cre) | Greater sensitivity to acute nociceptive stimuli | Hasue et al., 2005 |
| Cardiomyocyte ET-1−/− | Cardiomyocytes (alpha-myosin heavy chain -Cre) | Shorter life span; age-associated reduction in cardiac function | Zhao et al., 2006 |
| Smooth muscle ET-1−/− | Smooth muscle protein 22-Cre | Normal right ventricular systolic pressure basally; hypoxia leads to an attenuated increase in right ventricular systolic pressure compared with control mice | Kim et al., 2015 |
| VEETKO | Endothelium (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 feeding | Kisanuki et al., 2010; Adiarto et al., 2012; Arfian et al., 2012; Heiden et al., 2014; Heimlich et al., 2015 |
| Collecting duct ET-1−/− | AQP2-Cre | Elevated blood pressure; salt-sensitive hypertension; impaired ability to excrete water | Ahn et al., 2004; Ge et al., 2005a, 2007, 2008b |
| ET-2 | |||
| ET-2−/− | Whole body | Growth retardation; internal starvation; severe hypothermia; lung dysfunction; death at an early age | Chang et al., 2013 |
| inducible ET-2−/− knockout | Whole body (CAGGCre-ER) | Reduced weight gain; reduced lipid deposition; mild hypothermia | Chang et al., 2013 |
| Intestinal epithelium ET-2−/− | Villin-Cre | Normal growth and blood glucose level | Chang et al., 2013 |
| Neuron ET-2−/− | Nestin-Cre | Normal core temperature; greater sensitivity to acute nociceptive stimuli | Chang et al., 2013 |
| ET-3 | |||
| ET-3−/− | Whole body | Aganglionic megacolon; coat color spotting; normotensive and normal baroreflex sensitivity; death at an early age | Baynash et al., 1994; Kuwaki et al., 2002 |
| ls/ls | Whole body, natural mutation in the ET-3 gene | Aganglionic megacolon; white spotting coat | Rice et al., 2000 |
| ls/ls DβH-ET-3 | Naturally ET-3 deficient but ET-3 overexpressed in nerves (insertion with dopamine-β-hydroxylase promoter) | Reduction in white spotting coat; rescued from megacolon | Rice et al., 2000 |
| Piebald lethal s’/s’ | Natural deletion of the ETB gene from the whole body | Aganglionic megacolon; white spotting coat | Hosoda et al., 1994 |
| ETA | |||
| ETA−/− | Whole body | Craniofacial and cardiovascular defects: lethal minutes after birth | Clouthier 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 dysfunction | Kedzierski et al., 2003; Zhang et al., 2012 |
| Smooth muscle ETA−/− | Smooth muscle protein 22-Cre | Defects of arterial network, mandibular and thymus structure; death at an early age | Donato et al., 2014 |
| Collecting duct ETA−/− | AQP2-Cre | Normotensive; impaired ability to excrete water | Ge et al., 2005b |
| Whole nephron ETA−/− | Inducible (Pax8-rtTA and LC-1) | Normotensive; fluid retention during high salt intake | Stuart et al., 2012; Stuart et al., 2013 |
| ETB | |||
| ETB−/− | Whole body | Aganglionic megacolon; white spotting coat; death at an early age | Hosoda et al., 1994 |
| ETB-/s’ | Whole body, 1 allele naturally mutated | Systemic ETB deficiency; reduced incidence of megacolon; 50% white coat spotting; increased blood pressure; normal cardiac sympathetic and vagal activity; reduced brain and lung ETA | Ohuchi et al., 1999; Davenport and Kuc 2004; Kuc et al., 2006 |
| ETB−/−+ETB-DβH | ETB 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 dysfunction | Murakoshi et al., 2002; Quaschning et al., 2005 |
| ECETB−/− | Endothelium (Tie-2-Cre) | Endothelial dysfunction; normotensive; red cell congestion of the intrahepatic branch of portal vein | Bagnall et al., 2006; Kelland et al., 2010b; Ling et al., 2012 |
| Collecting duct ETB−/− | AQP2-Cre | Elevated blood pressure; increased ENaC activity; salt-sensitive hypertension | Ge et al., 2006; Bugaj et al., 2012 |
| Collecting duct ETA−/−/ETB−/− | AQP2-Cre | Elevated blood pressure; increased ENaC activity; salt-sensitive hypertension | Ge et al., 2008a; Bugaj et al., 2012 |