Cardiovascular beta-adrenergic signaling Maturation and programming effects of hypoxia in a chicken model

Sammanfattning: Despite the importance of ?-adrenergic receptors (?ARs) in cardiovascular disease, not much is known about how prenatal hypoxia effects ?AR signaling in the postnatal animal. Thus, the aim of this thesis was to characterize the pre- and postnatal maturation of the cardiovascular ?ARs and the effects of chronic prenatal hypoxia on ?AR signaling in the embryo and adult animal using the chicken as experimental model.?ARs 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, ?1AR and ?2AR, whose main ligands are the biogenic catecholamines epinephrine and norepinephrine. When stimulated, ?ARs 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. ?2ARs 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 ?ARs desensitize and downregulate in the case of prolonged elevation of catecholamines. This blunts the cardiovascular response and the mechanisms behind desensitization/downregulation, including the ?2AR 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 ?AR 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 ?AR sensitization, but causes desensitization postnatally suggesting that there is a hypoxia-induced “programming” effect on adult ?-adrenoceptor function, 3) the adult ?AR desensitization following prenatal hypoxia is linked to a decrease in ?1AR/?2AR ratio, a decrease in cAMP following ?AR 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 ?AR 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 ?AR system in the adult. The latter indicates that the ?AR system is an important factor in studying hypoxic developmental programming of adult cardiovascular disease.