title: Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene.
abstract: BACKGROUND
  Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. Levels of AM are markedly increased in the fetoplacental circulation during pregnancy, although its function there remains unknown. To clarify the physiological functions of AM, we chose a gene-targeting strategy in mice.
  
  
  RESULTS
  Targeted null mutation of the AM gene is lethal in utero: the mortality rate among AM(-/-) embryos was >80% at E13.5. The most apparent abnormality in surviving AM(-/-) embryos at E13.5 to E14.0 was severe hemorrhage, readily observable under the skin and in visceral organs. Hemorrhage was not detectable at E12.5 to E13.0, although the yolk sac lacked well-developed vessels. Electron microscopic examination showed endothelial cells to be partially detached from the basement structure at E12.5 in vitelline vessels and hepatic capillaries, which allowed efflux of protoerythrocytes through the disrupted barrier. The basement membrane was not clearly recognizable in the aorta and cervical artery, and the endothelial cells stood out from the wall of the lumen, only partially adhering to the basement structure. AM(+/-) mice survived to adulthood but exhibited elevated blood pressures with diminished nitric oxide production.
  
  
  CONCLUSIONS
  AM is indispensable for the vascular morphogenesis during embryonic development and for postnatal regulation of blood pressure by stimulating nitric oxide production.
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, and Institute for Adult Disease, Asahi Life Foundation, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shindo
authors.forename: Y
authors.initials: Y
authors.lastname: Kurihara
authors.forename: H
authors.initials: H
authors.lastname: Nishimatsu
authors.forename: N
authors.initials: N
authors.lastname: Moriyama
authors.forename: M
authors.initials: M
authors.lastname: Kakoki
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Imai
authors.forename: A
authors.initials: A
authors.lastname: Ebihara
authors.forename: T
authors.initials: T
authors.lastname: Kuwaki
authors.forename: K H
authors.initials: KH
authors.lastname: Ju
authors.forename: N
authors.initials: N
authors.lastname: Minamino
authors.forename: K
authors.initials: K
authors.lastname: Kangawa
authors.forename: T
authors.initials: T
authors.lastname: Ishikawa
authors.forename: M
authors.initials: M
authors.lastname: Fukuda
authors.forename: Y
authors.initials: Y
authors.lastname: Akimoto
authors.forename: H
authors.initials: H
authors.lastname: Kawakami
authors.forename: T
authors.initials: T
authors.lastname: Imai
authors.forename: H
authors.initials: H
authors.lastname: Morita
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
authors.forename: R
authors.initials: R
authors.lastname: Nagai
authors.forename: Y
authors.initials: Y
authors.lastname: Hirata
authors.forename: H
authors.initials: H
authors.lastname: Kurihara
mesh_terms: D053607:Adrenomedullin; D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities* / Q000473:pathology / Q000648:ultrastructure; D018376:Cardiovascular Abnormalities / Q000473:pathology*; D020964:Embryo Loss / Q000209:etiology / Q000473:pathology; D004730:Endothelium, Vascular / Q000196:embryology / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D018390:Gene Targeting; D005804:Genes, Lethal; D005838:Genotype; D006439:Hemodynamics / Q000235:genetics; D006470:Hemorrhage / Q000196:embryology / Q000235:genetics / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006973:Hypertension / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D007178:Inbreeding; D007260:Infusion Pumps; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D011994:Recombinant Proteins / Q000008:administration & dosage; D014817:Vitelline Membrane / Q000098:blood supply / Q000196:embryology / Q000473:pathology
chemical_list: D010455:Peptides; D011994:Recombinant Proteins; D053607:Adrenomedullin; D009569:Nitric Oxide