liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Chronic prenatal hypoxia sensitizes beta-adrenoceptors in the embryonic heart but causes postnatal desensitization
Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
2009 (English)In: AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, ISSN 0363-6119, Vol. 297, no 2, R258-R264 p.Article in journal (Refereed) Published
Abstract [en]

Prenatal hypoxia in mammals causes fetal growth restriction and catecholaminergic overstimulation that, in turn, alter signaling pathways associated with adrenergic receptors. beta-Adrenoceptors (beta-ARs) are essential for fetal cardiac development and regulation of cardiac contractility. We studied the effects of chronic prenatal hypoxia on cardiac beta-AR signaling and the incidence of alterations in the juvenile beta-AR system due to the embryonic treatment. We measured functional beta-AR density (B-max) through binding with [H-3]CGP-12177 and the effect of agonists on beta-AR-dependent contractility (pEC(50)) through concentration-response curves to epinephrine. Eggs from broiler chickens were incubated in normoxia (N, 21% O-2) or chronic hypoxia (H, 14% O-2). Cardiac tissue from embryos and juveniles was used (15 and 19 day of embryonic development and 14 and 35 days posthatching, E19, E15, P14, and P35, respectively). Relative cardiac enlargement was found in the hypoxic groups at E15, E19, and P14, but not P35. B-max significantly decreased in E19H. Bmax more than doubled posthatching but decreased from P14 to P35. The sensitivity to epinephrine was lower in E19N compared with E15N, but hypoxia increased the sensitivity to agonist in both E15H and E19H. Despite maintained receptor density, the P35H juvenile displayed a decreased sensitivity to beta-AR agonist, something that was not seen in P14H. The postnatal decrease in beta-AR sensitivity as an effect of chronic prenatal hypoxia, without a concomitant change in beta-AR density, leads us to conclude that the embryonic hypoxic challenge alters the future progression of beta-AR signaling and may have important implications for cardiovascular function in the adult.

Place, publisher, year, edition, pages
2009. Vol. 297, no 2, R258-R264 p.
Keyword [en]
beta-adrenergic; embryonic development; hypoxia; receptor density; receptor sensitivity
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-20149DOI: 10.1152/ajpregu.00167.2009OAI: oai:DiVA.org:liu-20149DiVA: diva2:233663
Available from: 2009-09-01 Created: 2009-08-31 Last updated: 2011-02-04Bibliographically approved
In thesis
1. Cardiovascular beta-adrenergic signaling: Maturation and programming effects of hypoxia in a chicken model
Open this publication in new window or tab >>Cardiovascular beta-adrenergic signaling: Maturation and programming effects of hypoxia in a chicken model
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Despite the importance of β-adrenergic receptors (βARs) in cardiovascular disease, not much is known about how prenatal hypoxia effects βAR signaling in the postnatal animal. Thus, the aim of this thesis was to characterize the pre- and postnatal maturation of the cardiovascular βARs and the effects of chronic prenatal hypoxia on βAR signaling in the embryo and adult animal using the chicken as experimental model.

βARs belong to the seven-transmembrane receptor family of G-protein coupled receptors and are crucial for cardiovascular development, growth and regulation. In the cardiovascular system there are two dominant  subtypes, β1AR and β2AR, whose main ligands are the biogenic catecholamines epinephrine and norepinephrine. When stimulated, βARs primarily couple to the stimulatory G-protein (Gas) that stimulates adenylyl cyclase to convert ATP to cAMP. cAMP increases ino- and chronotropy of the heart and causes relaxation of blood vessels. β2ARs also have the ability to switch to inhibitory G-protein (Gi) signaling that decreases the cAMP production. To protect the cardiovascular system from overstimulation, the βARs desensitize and downregulate in the case of prolonged elevation of catecholamines. This blunts the cardiovascular response and the mechanisms behind desensitization/downregulation, including the β2AR switch to Gi signaling, are closely linked to cardiovascular disease and are of immense importance in medical therapeutics.

Hypoxic stress releases catecholamines and thereby triggers βAR responses and desensitization/downregulation mechanisms. Hypoxia quite commonly occurs in utero and it is well known that prenatal insults, like malnutrition or hypoxia, are coupled to an increased risk of developing adult cardiovascular disease. This is referred to as developmental programming and constitutes an important and modern field of research.

In this thesis, I show that; 1) the developmental trajectory for organ growth, especially the heart, is affected by hypoxia, 2) chronic prenatal hypoxia causes cardiac embryonic βAR sensitization, but causes desensitization postnatally suggesting that there is a hypoxia-induced “programming” effect on adult β-adrenoceptor function, 3) the adult βAR desensitization following prenatal hypoxia is linked to a decrease in β1AR/β2AR ratio, a decrease in cAMP following βAR stimulation with isoproterenol and an increase in Gas, 4) the chorioallantoic (CA) membrane arteries display hypoxic vasoconstriction, but lack 8-adrenergic reactivity and 5) hypotension of the chronically hypoxic chicken embryo is linked to a potent βAR relaxation of the CA vasculature and an increased AR sensitivity of the systemic arteries with no changes in heart rate.

In conclusion, chronic prenatal hypoxia causes growth restriction, re-allocation and has programming effects on the βAR system in the adult. The latter indicates that the βAR system is an important factor in studying hypoxic developmental programming of adult cardiovascular disease.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. 48 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1330
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-65367 (URN)978-91.7393-352-0 (ISBN)
Public defence
2010-09-10, Planck, Hus E, Campus Valla, Linköpings universitet, Linköping, 09:15 (English)
Opponent
Supervisors
Available from: 2011-02-04 Created: 2011-02-04 Last updated: 2012-11-19Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Authority records BETA

Lindgren, IsaAltimiras, Jordi

Search in DiVA

By author/editor
Lindgren, IsaAltimiras, Jordi
By organisation
Zoology The Institute of Technology
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 116 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf