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Cardiovascular beta-adrenergic signaling: Maturation and programming effects of hypoxia in a chicken model
Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
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: urn:nbn:se:liu:diva-65367ISBN: 978-91.7393-352-0 OAI: oai:DiVA.org:liu-65367DiVA: diva2:395205
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
List of papers
1. Sensitivity of organ growth to chronically low oxygen levels during incubation in Red Junglefowl and domesticated chicken breeds
Open this publication in new window or tab >>Sensitivity of organ growth to chronically low oxygen levels during incubation in Red Junglefowl and domesticated chicken breeds
2011 (English)In: Poultry Science, ISSN 0032-5791, E-ISSN 1525-3171, Vol. 90, no 1, 126-135 p.Article in journal (Refereed) Published
Abstract [en]

Genetic selection programs have imposed large phenotypic changes in domesticated chicken breeds that are also apparent during embryonic development. Broilers, for example, have a faster growth rate before hatching in comparison with White Leghorns, indicating that the allocation of resources toward different functions already begins before hatching. Therefore, we hypothesized that embryonic organ growth would follow different developmental trajectories and would be differentially affected by an oxygen shortage during incubation. Heart, brain, and liver growth were studied in broiler, White Leghorn, and Red Junglefowl embryos at embryonic (E) ages E11, E13, E15, E18, and E20, and the results were fitted to growth allometric equations to determine the degree of organ stunting or sparing caused by low oxygen during incubation. Hypoxia caused a 3-fold larger mortality in Red Junglefowl than in the domesticated breeds, with a similar impairment of embryonic growth of 18%, coupled with a reduction in yolk utilization of 56%. Relative brain size was not affected by hypoxia in any breed, but a substantial stunting effect was observed for the liver and heart at late embryonic ages, with marked differences between breeds. In Red Junglefowl, only the heart was stunted. In White Leghorns, only the liver was stunted, and in broilers, both organs were stunted. These results can be explained in terms of the selection pressure on long-term production traits (reproductive effort) in White Leghorns, requiring a more efficient lipid metabolism, compared with the selection pressure on shorter-term production traits (growth) in broilers, requiring overall metabolic turnover and convective nutrient delivery to all tissues. At the same time, a remarkable sparing of the heart was observed in broilers and Red Junglefowl between E11 and E15, which suggests that cardiac growth can be manipulated during embryonic development. This result could be relevant for manipulating the phenotype of the heart for management purposes at a developmental stage when the bird is most versatile and phenotypically malleable.

Place, publisher, year, edition, pages
Poultry Science Association, 2011
Keyword
broiler, domestication, organ growth, hypoxia, cardiovascular development
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-64572 (URN)10.3382/ps.2010-00996 (DOI)000285504700016 ()
Available from: 2011-01-28 Created: 2011-01-28 Last updated: 2017-12-11
2. Chronic prenatal hypoxia sensitizes beta-adrenoceptors in the embryonic heart but causes postnatal desensitization
Open this publication in new window or tab >>Chronic prenatal hypoxia sensitizes beta-adrenoceptors in the embryonic heart but causes postnatal desensitization
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.

Keyword
beta-adrenergic; embryonic development; hypoxia; receptor density; receptor sensitivity
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-20149 (URN)10.1152/ajpregu.00167.2009 (DOI)
Available from: 2009-09-01 Created: 2009-08-31 Last updated: 2011-02-04Bibliographically approved
3. Postnatal β-adrenergic desensitization caused by chronic prenatal hypoxia is linked to anincrease in Gas and decreased β1AR/β2AR ratio
Open this publication in new window or tab >>Postnatal β-adrenergic desensitization caused by chronic prenatal hypoxia is linked to anincrease in Gas and decreased β1AR/β2AR ratio
(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
Identifiers
urn:nbn:se:liu:diva-65357 (URN)
Available from: 2011-02-04 Created: 2011-02-04 Last updated: 2011-02-04
4. Reactivity of chicken chorioallantoic arteries, avian homologue of human fetoplacental arteries
Open this publication in new window or tab >>Reactivity of chicken chorioallantoic arteries, avian homologue of human fetoplacental arteries
2010 (English)In: Journal of Physiology and Pharmacology, ISSN 0867-5910, E-ISSN 1899-1505, Vol. 61, no 5, 619-628 p.Article in journal (Refereed) Published
Abstract [en]

The reactivity of human fetoplacental arteries is regulated by humoral and local factors of maternal and fetal origin. The chorioallantoic (CA) arteries of bird embryos are homologous to fetoplacental arteries and fulfill the same gas-exchange purpose without maternal influences, but their reactivity has not been studied in detail. In the present study we hypothesized that CA arteries would respond to vasoactive factors similarly to fetoplacental arteries and the response would change during development between maximal vascular CA expansion (15 of the 21 days incubation period) and prior to hatching. Therefore, we analyzed the reactivity of third order arteries (similar to 200 mu m) from the CA membrane of 15 and 19 day chicken embryos. CA arteries contracted in response to K+, the thromboxane A(2) mimetic U46619, endothelin-1, acetylcholine and acute hypoxia, but showed no reaction to alpha-adrenergic stimulation (phenylephrine). The nitric oxide donor sodium nitroprusside, the adenylyl cyclase agonist forskolin, and the beta-adrenergic agonist isoproterenol relaxed CA arteries precontracted with K+ or U46619. The contraction evoked by acetylcholine and the relaxations evoked by sodium nitroprusside and isoproterenol decreased with incubation age. In conclusion, CA arteries share many characteristics with human fetoplacental arteries, such as pronounced relaxation to beta-adrenergic stimuli and hypoxic vasoconstriction. Our study will be the foundation for future studies to explain disparate and common responses of the CA and fetoplacental vasculature.

Place, publisher, year, edition, pages
Polish Physiological Society, 2010
Keyword
beta-adrenergic agonist, chicken embryo, chorioallantoic membrane, hypoxic vasoconstriction, thromboxane A(2), vasoreactivity
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-63392 (URN)000284790500013 ()
Available from: 2010-12-17 Created: 2010-12-17 Last updated: 2017-12-11
5. Hypotension in the chronically hypoxic chicken embryo is related to the β-adrenergic response of chorioallantoic and femoral arteries and not to bradycardia
Open this publication in new window or tab >>Hypotension in the chronically hypoxic chicken embryo is related to the β-adrenergic response of chorioallantoic and femoral arteries and not to bradycardia
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
Keyword
Prenatal hypoxia, hypoxic hypotension, chorioallantoic membrane, β-adrenoceptors, α-adrenoceptors
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-65359 (URN)10.1152/ajpregu.00458.2010 (DOI)000295881600031 ()
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: 2017-12-11

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