Hypertension Programmed in Adult Hens by Isolated Effects of Developmental Hypoxia In Ovo

Abstract

In mammals, pregnancy complicated by chronic hypoxia can program hypertension in the adult offspring. However, mechanisms remain uncertain because the partial contributions of the challenge on the placenta, mother, and fetus are difficult to disentangle. Here, we used chronic hypoxia in the chicken embryo—an established model system that permits isolation of the direct effects of developmental hypoxia on the cardiovascular system of the offspring, independent of additional effects on the mother or the placenta. Fertilized chicken eggs were exposed to normoxia (N; 21% O 2 ) or hypoxia (H; 13.5%–14% O 2 ) from the start of incubation (day 0) until day 19 (hatching, ≈day 21). Following hatching, all birds were maintained under normoxic conditions until ≈6 months of adulthood. Hypoxic incubation increased hematocrit (+27%) in the chicken embryo and induced asymmetrical growth restriction (body weight, −8.6%; biparietal diameter/body weight ratio, +7.5%) in the hatchlings (all P <0.05). At adulthood (181±4 days), chickens from hypoxic incubations remained smaller (body weight, −7.5%) and showed reduced basal and stimulated in vivo NO bioavailability (pressor response to NG-nitro-L-arginine methyl ester, −43%; phenylephrine pressor response during NO blockade, −61%) with significant hypertension (mean arterial blood pressure, +18%), increased cardiac work (ejection fraction, +12%; fractional shortening, +25%; enhanced baroreflex gain, +456%), and left ventricular wall thickening (left ventricular wall volume, +36%; all P <0.05). Therefore, we show that chronic hypoxia can act directly on a developing embryo to program hypertension, cardiovascular dysfunction, and cardiac wall remodeling in adulthood in the absence of any maternal or placental effects.

Mitochondria antioxidant protection against cardiovascular dysfunction programmed by early‐onset gestational hypoxia

“…Previous studies have also confirmed that embryonic and fetal development under chronic hypoxic conditions can program increased cardiovascular responsiveness to sympathetic stimulation and myocardial contractility in adult offspring, enhancing cardiac systolic function 8,15,66‐68 . The term cardiac sympathetic dominance describes an increased ratio of the maximal cardiac response to isoprenaline relative to that of carbachol 8,15,22,39,67,68 . It has been suggested that this cardiac sympathetic dominant response is necessary to overcome programmed increases in peripheral vasoconstriction and cardiac afterload, thereby maintaining cardiac output in adult offspring of hypoxic pregnancy 8,15,39,67,68 .…”

“…8,15,[66][67][68] The term cardiac sympathetic dominance describes an increased ratio of the maximal cardiac response to isoprenaline relative to that of carbachol. 8,15,22,39,67,68 It has been suggested that this cardiac sympathetic dominant response is necessary to overcome programmed increases in peripheral vasoconstriction and cardiac afterload, thereby maintaining cardiac output in adult offspring of hypoxic pregnancy. 8,15,39,67,68 However, data in the present study reveal that a programmed increase in cardiac sympathetic dominance can occur in the absence of systemic hypertension in adult offspring of hypoxic pregnancy.…”

“…The maximum and minimum first derivatives of the LV pressure (dP/dt max and dP/dt min ) were calculated. Contractility index, an index of systolic function, was calculated as the value for dP/dt max normalized to mean pressure at the point of dP/dt max 39 . The cardiac responsiveness to the muscarinic agonist Carbachol (carbamylcholine chloride, Sigma‐Aldrich Co. Ltd, Poole, UK; range, 10 −10 to 10 −6 M) and the β 1 adrenoreceptor agonist Isoprenaline ((−)‐Isoprenaline (+)‐bitartrate salt, Sigma‐Aldrich Co. Ltd, Poole, UK; range, 10‐11 to 10‐7 M) were investigated, as described before 15,22 .…”

“…Contractility index, an index of systolic function, was calculated as the value for dP/dt max normalized to mean pressure at the point of dP/ dt max . 39 The cardiac responsiveness to the muscarinic agonist Carbachol (carbamylcholine chloride, Sigma-Aldrich Co. Ltd, Poole, UK; range, 10 -10 to 10 -6 M) and the β 1 adrenoreceptor agonist Isoprenaline ((-)-Isoprenaline (+)-bitartrate salt, Sigma-Aldrich Co. Ltd, Poole, UK; range, 10-11 to 10-7 M) were investigated, as described before. 15 , 22 The ratio of the maximal LV contractile (ionotropic) response to Isoprenaline relative to that of Carbachol is an established measure of cardiac sympathetic dominance.…”

Breath of Life: Heart Disease Link to Developmental Hypoxia

“…Data from Giussani et al 46 , 85 with permission (Copyright ©2001, Springer Nature; Copyright ©2007, The Physiological Society) and Soria et al 47 (Copyright ©2013, Springer Nature). Photos reprinted from Itani et al 97 with permission.…”