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Hypotension in the chronically hypoxic chicken embryo is related to the β-adrenergic response of chorioallantoic and femoral arteries and not to bradycardia
Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
Biology Department, University of North Dakota, USA.
Department of Pediatrics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+), The Netherlands.
Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
2011 (English)In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 301, no 4, R1161-R1168 p.Article in journal (Refereed) Published
Abstract [en]

Prolonged fetal hypoxia leads to growth restriction and can cause detrimental pre- and postnatal alterations. The embryonic chicken is a valuable model to study such effects of prenatal hypoxia, but little is known about long-term hypoxic effects on cardiovascular regulation in the chicken embryo. We investigated heart rate and blood pressure responses to chronic prenatal hypoxia in the chicken embryo (19 days) and hypothesized that it would exhibit hypotension due to bradycardia and βAR-mediated relaxation of the systemic (femoral) and/or the chorioallantoic (CA) arteries. We first measured heart rate (HR) and blood pressure (BP) in 19 day embryos incubated from day 0 in normoxia or hypoxia (14-15% O2). Secondly, we studied β-adrenoceptor (βAR)-mediated contraction, relaxation to the β-adrenoceptor (βAR) agonist isoproterenol and relaxation to forskolin in femoral and CA arteries using wire myography techniques. Chronic hypoxia caused a close to significant hypotension compared to the controls (Mean arterial pressure 3.19±0.18 vs. 2.59±0.13 kPa, normoxia vs. hypoxia respectively, P=0.056), but not bradycardia. All vessels relaxed in response to βAR stimulation with isoproterenol, but the CAM arteries completely lacked an βAR response. Furthermore, hypoxia increased the sensitivity of femoral (but not CA arteries) to isoproterenol. Hypoxia also increased the responsiveness of femoral arteries to the adenylate cyclase activator forskolin. In conclusion, hypotension in chronically hypoxic chicken embryos is more likely the consequence of elevated levels of circulating catecholamines acting on vascular beds with exclusive (CA arteries) or exacerbated (femoral arteries) βAR-mediated relaxation, rather than a consequence of bradycardia.

Place, publisher, year, edition, pages
American Physiological Society , 2011. Vol. 301, no 4, R1161-R1168 p.
Keyword [en]
Prenatal hypoxia, hypoxic hypotension, chorioallantoic membrane, β-adrenoceptors, α-adrenoceptors
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-65359DOI: 10.1152/ajpregu.00458.2010ISI: 000295881600031OAI: oai:DiVA.org:liu-65359DiVA: diva2:395191
Note
Funding agencies|FORMAS, the Swedish Research Council for Environment||Agricultural Sciences and Spatial Planning||Wallenberg Foundation||Available from: 2011-02-04 Created: 2011-02-04 Last updated: 2011-11-04
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

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Lindgren, IsaAltimiras, Jordi

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