doi: 10.1161/hc4101.097111
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(Circulation. 2001;104:1964.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Vascular Abnormalities and Elevated Blood Pressure in Mice Lacking Adrenomedullin Gene
From the Department of Cardiovascular Medicine (T.S., Y.K., M.K., Y.W., Y.I., T. Imai, H.M., R.N., Y.H.), Department of Urology (H.N., N. Moriyama), Department of Physiology (K.-H.J.), and Department of Pathology (T. Ishikawa), Graduate School of Medicine, University of Tokyo, and Institute for Adult Disease, Asahi Life Foundation, Tokyo (A.E.); Department of Physiology, School of Medicine, Chiba University, Chiba (T.K.); National Cardiovascular Center Research Institute, Osaka (N. Minamino, K.K.); Department of Anatomy, Kyorin University, Tokyo (M.F., Y.A., H. Kawakami); Hospital International Medical Center of Japan, Tokyo (Y.Y.); and Division of Integrative Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, and CREST (Core Research for Evolutional Science and Technology), Japan Science and Technology Corp (H. Kurihara), Japan.
Correspondence to Hiroki Kurihara, MD, PhD, Division of Integrative Cell Biology, Department of Embryogenesis, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan. E-mail kurihara{at}kaiju.medic.kumamoto-u.ac.jp
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.
Methods and 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.
Key Words: vasculature • endothelium • blood pressure
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|
|
|
|
|
|
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|
|
|
|
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|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|