Cross-interactions between CO and NO signaling in microvascular endothelium

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17500261
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Keio University
• Principal Investigator: KAJIMURA Mayumi Keio University, School of Medicine, Assistant Professor, 医学部, 講師 (10327497)
• Co-Investigator(Kenkyū-buntansha): ISHIKAWA Mami Jichi Medical College, School of Medicine, Instructor, 医学部, 助手 (60212859)
• Project Period (FY): 2005 – 2006
• Keywords: heme oxygenase / carbon monoxide / nitric oxide / cerebral circulation / nitric oxide synthase / pial circulation

Research Abstract

Carbon monoxide (CO) is synthesized endogenously by heme oxygenase (HO) which degrades heme to biliverdin-IXα. Like nitric oxide (NO), CO has a vasodilatory property in the liver where endogenous NO production appears low. However, in the brain producing relatively high NO, how these gaseous monoxides interact each other to control cerebrovascular tone is unknown. Here we show that CO derived from HO acts as a tonic regulator against NO-dependent vasodilatation in the adult rat brain. We found that suppressing endogenous CO caused an increase in arteriolar diameter that was accompanied by an increase in local NO generation. We examined further if such an inhibitory function of CO on NO generation is mediated through the ability of CO to bind the prosthetic heme of gas-producing enzymes. Using cultured porcine aortic endothelial cells (PAECs), we measured NO generation by an NO-specific fluorescent dye. Treatment with CO-releasing molecule attenuated the time-dependent elevation of NO generation. This effect of CO to suppress NO generation was cancelled by exposing PAECs to white light raising a possibility that CO directly targets The ferrous heme of NOS3 to inhibit the catalytic activity. Furthermore, immunohistochemical analyses of the rat brain showed that HO-2 occurred in neurons and arachnoid trabecullar cells where NOS1 resided, and also in vascular endothelium expressing NOS3, suggesting colocalization of CO-and NO-generating sites. Our results demonstrate an importance of spatial relationship among the gas-producing enzymes and their reception systems in evaluating roles of the two gases.

Research Products

• [Journal Article] Real time imaging of mechanically injured-femoral artery in mouse revealed a biphasic pattern of leukocyte accumulation (2006)
  • Author(s): Osaka M., Hagita S., Haraguchi M., Kajimura M., Suematsu M., Yoshida M
  • Journal Title: American Journal of Physiology : Heart and Circulatory Physiology Dec 15(Epub ahead of print) Pages: 28
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Angiotensin II type1 receptor signaling contributes to platelet-leukocyte-endothelial cell interactions in the cerebral microvasculature (2006)
  • Author(s): Ishikawa M, Sekizuka E, Yamaguchi N, Nakadate H, Terao S, Granger DN, Minamitani H
  • Journal Title: American Journal of Physiology : Heart and Circulatory Physiology Dec 9(Epub ahead of print) Pages: 36
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Real time imaging of mechanically injured-femoral artery in mouse revealed a biphasic pattern of leukocyte accumulation. (2006)
  • Author(s): Osaka M., Hagita S., Haraguchi M., Kajimura M., Suematsu M., Yoshida M.
  • Journal Title: American Journal of Physiology : Heart and Circulatory Physiology (Epub ahead of print)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] AngiotensinII type1 receptor signaling contributes to platelet-leukocyte-endothelial cell interactions in the cerebral microvasculature. (2006)
  • Author(s): Ishikawa M, Sekizuka E, Yamaguchi N, Nakadate H, Terao S, Granger DN, Minamitani H.
  • Journal Title: American Journal of Physiology : Heart and Circulatory Physiology 5(Epub ahead of print)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Carbon monoxide from heme oxygenase-2 is a tonic regulator against NO-dependent vasodilatation in the adult rat cerebral microcirculation (2005)
  • Author(s): Ishikawa, M., Kajimura, M., Suematsu, M.et al.
  • Journal Title: Circulation Research 12 Pages: el04-e114
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] CD40/CD40 ligand signaling in mouse cerebral microvasculature after focal ischemia/reperfusion (2005)
  • Author(s): Ishikawa, M., Vowinkel, T., Stokes, K.Y., Arumugam, T.V., Yilmaz, G., Nanda, A., Granger, D.N.
  • Journal Title: Circulation 111(13) Pages: 1690-1696
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Carbon monoxide from heme oxygenase-2 is a tonic regulator against nitric oxide-dependent vasodilatation in the adult rat cerebral microcirculation. * the first authorship (2005)
  • Author(s): Ishikawa M., Kajimura M., Adachi T., Maruyama K., Goda N., Suematsu M.et al.
  • Journal Title: Circulation Research 97 Pages: e104-e114
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CD40/CD40 ligand signaling in mouse cerebral microvasculature after focal ischemia/reperfusion (2005)
  • Author(s): Ishikawa, M., Vowinkel, T., Stokes, K.Y., Arumugam, T.V., Yilmaz, G., Nanda, A., Granger, D.N.
  • Journal Title: Circulation 111 Pages: 1690-1696
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 細胞工学 (2006)
  • Author(s): 末松 誠, 梶村 眞弓, 足立 健
  • Total Pages: 216
  • Publisher: 秀潤社
  • Description: 「研究成果報告書概要(和文)」より