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Postnatal β-adrenergic desensitization caused by chronic prenatal hypoxia is linked to anincrease in Gas and decreased β1AR/β2AR ratio
Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Prenatal hypoxia leads to growth restriction and increased risk of adult cardiovascular disease. We have previously demonstrated that prenatal hypoxia desensitizes the 5 week chicken heart, but has no effect in the 2 week heart. This indicates that there is a programming effect of prenatal hypoxia on βAR signaling. It has been shown in a rat model that the β1AR/β2AR ratio and increased Gai expression is related to decreased βAR sensitivity measured by cAMP production after βAR stimulation. Thus, the aim of this study was to determine whether the observed decrease in βAR sensitivity in the prenatally hypoxic 5 week chicken heart is linked to changes in β1AR/β2AR ratio and Gai expression and what effects it has on the cAMP accumulation due to βAR stimulation.

We incubated eggs in normoxia (N, 20.95% O2) or hypoxia from day 0 (H, 14% O2) and raised the post-hatchlings to 5 weeks of age in normoxic conditions. The hearts were sampled and the β1AR/β2AR ratio in intact heart slices was assessed through competitive binding of [3H]CGP-12177 with specific β1AR or β2AR blockers (CGP-20712A and ICI-118,551 respectively). Gas and Gai expression was assessed by Western blot and an immunoassay was used to determine the cAMP accumulation after βAR stimulation with isoproterenol. We found that there is indeed a decrease in β1AR/β2AR ratio. Surprisingly, Gas increased in prenatally hypoxic hearts and not Gai as hypothesized. cAMP levels after isoproterenol stimulation of βARs was lower in H than in N.

In conclusion, the desensitization of βARs to epinephrine in 5 week chickens exposed to prenatal hypoxia was confirmed by significantly lower cAMP production in response to βAR stimulation compared to the controls. Furthermore, the β1AR/β2AR ratio in prenatally hypoxic animals was decreased similarly to the β1AR/β2AR ratio change seen in heart failure. Gas expression was increased, but again considering the lower cAMP accumulation in response to βAR stimulation, the increased Gas seems to be inactive. We speculate that the 5 week chicken exposed to prenatal hypoxia might be displaying early signs of heart failure.

National Category
Natural Sciences
URN: urn:nbn:se:liu:diva-65357OAI: diva2:395186
Available from: 2011-02-04 Created: 2011-02-04 Last updated: 2011-02-04
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.
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1330
National Category
Natural Sciences
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)
Available from: 2011-02-04 Created: 2011-02-04 Last updated: 2012-11-19Bibliographically approved

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