title: Importance of Endogenous Atrial and Brain Natriuretic Peptides in Murine Embryonic Vascular and Organ Development.
abstract: Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) bind to the receptor guanylyl cyclase (GC)-A, leading to diuresis, natriuresis, and blood vessel dilation. In addition, ANP and BNP have various angiogenic properties in ischemic tissue. When breeding mice devoid of GC-A, we noted significant skewing of the Mendelian ratio in the offspring, suggesting embryonic lethality due to knockout of GC-A. Consequently, we here investigated the roles of endogenous ANP and BNP in embryonic neovascularization and organ morphogenesis. Embryos resulting from GC-A(-/-) × GC-A(+/-) crosses developed hydrops fetalis (HF) beginning at embryonic day (E)14.5. All embryos with HF had the genotype GC-A(-/-). At E17.5, 33.3% (12 of 36) of GC-A(-/-) embryos had HF, and all GC-A(-/-) embryos with HF were dead. Beginning at E16.0, HF-GC-A(-/-) embryos demonstrated poorly developed superficial vascular vessels and sc hemorrhage, the fetal side of the placenta appeared ischemic, and vitelline vessels on the yolk sac were poorly developed. Furthermore, HF-GC-A(-/-) embryos also showed abnormal constriction of umbilical cord vascular vessels, few cardiac trabeculae and a thin compact zone, hepatic hemorrhage, and poor bone development. Electron microscopy of E16.5 HF-GC-A(-/-) embryos revealed severe vacuolar degeneration in endothelial cells, and the expected 3-layer structure of the smooth muscle wall of the umbilical artery was indistinct. These data demonstrate the importance of the endogenous ANP/BNP-GC-A system not only in the neovascularization of ischemic tissues but also in embryonic vascular development and organ morphogenesis.
authors.affiliation: Department of Biochemistry (T.T., I.K., H.N., M.M.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiovascular Research (T.S., T.K.), Shinshu University Graduate School of Medicine, Shinshu, 565-8565 Japan; Department of Anatomy (H.K.), Kyorin University School of Medicine, Mitaka, Tokyo, 565-8565 Japan; Tissue Engineering and Regenerative Medicine (K.O.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiorenal and Cerebrovascular Medicine (M.K.), Kagawa University Faculty of Medicine, Kagawa, 565-8565 Japan; Kyoto University Graduate School of Medicine Medical Innovation Center (K.N.), Kyoto, 565-8565 Japan; and Director General (K.K.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokudome
authors.affiliation: Department of Biochemistry (T.T., I.K., H.N., M.M.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiovascular Research (T.S., T.K.), Shinshu University Graduate School of Medicine, Shinshu, 565-8565 Japan; Department of Anatomy (H.K.), Kyorin University School of Medicine, Mitaka, Tokyo, 565-8565 Japan; Tissue Engineering and Regenerative Medicine (K.O.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiorenal and Cerebrovascular Medicine (M.K.), Kagawa University Faculty of Medicine, Kagawa, 565-8565 Japan; Kyoto University Graduate School of Medicine Medical Innovation Center (K.N.), Kyoto, 565-8565 Japan; and Director General (K.K.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kishimoto
authors.affiliation: Department of Biochemistry (T.T., I.K., H.N., M.M.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiovascular Research (T.S., T.K.), Shinshu University Graduate School of Medicine, Shinshu, 565-8565 Japan; Department of Anatomy (H.K.), Kyorin University School of Medicine, Mitaka, Tokyo, 565-8565 Japan; Tissue Engineering and Regenerative Medicine (K.O.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiorenal and Cerebrovascular Medicine (M.K.), Kagawa University Faculty of Medicine, Kagawa, 565-8565 Japan; Kyoto University Graduate School of Medicine Medical Innovation Center (K.N.), Kyoto, 565-8565 Japan; and Director General (K.K.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shindo
authors.affiliation: Department of Biochemistry (T.T., I.K., H.N., M.M.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiovascular Research (T.S., T.K.), Shinshu University Graduate School of Medicine, Shinshu, 565-8565 Japan; Department of Anatomy (H.K.), Kyorin University School of Medicine, Mitaka, Tokyo, 565-8565 Japan; Tissue Engineering and Regenerative Medicine (K.O.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiorenal and Cerebrovascular Medicine (M.K.), Kagawa University Faculty of Medicine, Kagawa, 565-8565 Japan; Kyoto University Graduate School of Medicine Medical Innovation Center (K.N.), Kyoto, 565-8565 Japan; and Director General (K.K.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Kawakami
authors.affiliation: Department of Biochemistry (T.T., I.K., H.N., M.M.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiovascular Research (T.S., T.K.), Shinshu University Graduate School of Medicine, Shinshu, 565-8565 Japan; Department of Anatomy (H.K.), Kyorin University School of Medicine, Mitaka, Tokyo, 565-8565 Japan; Tissue Engineering and Regenerative Medicine (K.O.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiorenal and Cerebrovascular Medicine (M.K.), Kagawa University Faculty of Medicine, Kagawa, 565-8565 Japan; Kyoto University Graduate School of Medicine Medical Innovation Center (K.N.), Kyoto, 565-8565 Japan; and Director General (K.K.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan.
authors.forename: Teruhide
authors.initials: T
authors.lastname: Koyama
authors.affiliation: Department of Biochemistry (T.T., I.K., H.N., M.M.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiovascular Research (T.S., T.K.), Shinshu University Graduate School of Medicine, Shinshu, 565-8565 Japan; Department of Anatomy (H.K.), Kyorin University School of Medicine, Mitaka, Tokyo, 565-8565 Japan; Tissue Engineering and Regenerative Medicine (K.O.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiorenal and Cerebrovascular Medicine (M.K.), Kagawa University Faculty of Medicine, Kagawa, 565-8565 Japan; Kyoto University Graduate School of Medicine Medical Innovation Center (K.N.), Kyoto, 565-8565 Japan; and Director General (K.K.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Otani
authors.affiliation: Department of Biochemistry (T.T., I.K., H.N., M.M.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiovascular Research (T.S., T.K.), Shinshu University Graduate School of Medicine, Shinshu, 565-8565 Japan; Department of Anatomy (H.K.), Kyorin University School of Medicine, Mitaka, Tokyo, 565-8565 Japan; Tissue Engineering and Regenerative Medicine (K.O.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiorenal and Cerebrovascular Medicine (M.K.), Kagawa University Faculty of Medicine, Kagawa, 565-8565 Japan; Kyoto University Graduate School of Medicine Medical Innovation Center (K.N.), Kyoto, 565-8565 Japan; and Director General (K.K.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Nishimura
authors.affiliation: Department of Biochemistry (T.T., I.K., H.N., M.M.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiovascular Research (T.S., T.K.), Shinshu University Graduate School of Medicine, Shinshu, 565-8565 Japan; Department of Anatomy (H.K.), Kyorin University School of Medicine, Mitaka, Tokyo, 565-8565 Japan; Tissue Engineering and Regenerative Medicine (K.O.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiorenal and Cerebrovascular Medicine (M.K.), Kagawa University Faculty of Medicine, Kagawa, 565-8565 Japan; Kyoto University Graduate School of Medicine Medical Innovation Center (K.N.), Kyoto, 565-8565 Japan; and Director General (K.K.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan.
authors.forename: Mikiya
authors.initials: M
authors.lastname: Miyazato
authors.affiliation: Department of Biochemistry (T.T., I.K., H.N., M.M.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiovascular Research (T.S., T.K.), Shinshu University Graduate School of Medicine, Shinshu, 565-8565 Japan; Department of Anatomy (H.K.), Kyorin University School of Medicine, Mitaka, Tokyo, 565-8565 Japan; Tissue Engineering and Regenerative Medicine (K.O.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiorenal and Cerebrovascular Medicine (M.K.), Kagawa University Faculty of Medicine, Kagawa, 565-8565 Japan; Kyoto University Graduate School of Medicine Medical Innovation Center (K.N.), Kyoto, 565-8565 Japan; and Director General (K.K.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
authors.affiliation: Department of Biochemistry (T.T., I.K., H.N., M.M.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiovascular Research (T.S., T.K.), Shinshu University Graduate School of Medicine, Shinshu, 565-8565 Japan; Department of Anatomy (H.K.), Kyorin University School of Medicine, Mitaka, Tokyo, 565-8565 Japan; Tissue Engineering and Regenerative Medicine (K.O.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiorenal and Cerebrovascular Medicine (M.K.), Kagawa University Faculty of Medicine, Kagawa, 565-8565 Japan; Kyoto University Graduate School of Medicine Medical Innovation Center (K.N.), Kyoto, 565-8565 Japan; and Director General (K.K.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan.
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Biochemistry (T.T., I.K., H.N., M.M.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiovascular Research (T.S., T.K.), Shinshu University Graduate School of Medicine, Shinshu, 565-8565 Japan; Department of Anatomy (H.K.), Kyorin University School of Medicine, Mitaka, Tokyo, 565-8565 Japan; Tissue Engineering and Regenerative Medicine (K.O.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan; Department of Cardiorenal and Cerebrovascular Medicine (M.K.), Kagawa University Faculty of Medicine, Kagawa, 565-8565 Japan; Kyoto University Graduate School of Medicine Medical Innovation Center (K.N.), Kyoto, 565-8565 Japan; and Director General (K.K.), National Cerebral and Cardiovascular Research Center, Suita, Osaka, 565-8565 Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D018507:Gene Expression Regulation, Developmental; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D015160:Hydrops Fetalis / Q000235:genetics / Q000473:pathology / Q000662:veterinary; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D038081:Organogenesis; D011247:Pregnancy; D017461:Receptors, Atrial Natriuretic Factor / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C096161:KLF2 protein, human; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A