Long-Term High-Altitude Hypoxia and Alpha Adrenoceptor-Dependent Pulmonary Arterial Contractions in Fetal and Adult Sheep

Abstract

Autonomic innervation of the pulmonary vasculature triggers vasomotor contractility predominately through activation of alpha-adrenergic receptors (α-ARs) in the fetal circulation. Long-term hypoxia (LTH) modulates pulmonary vasoconstriction potentially through upregulation of α 1 -AR in the vasculature. Our study aimed to elucidate the role of α-AR in phenylephrine (PE)-induced pulmonary vascular contractility, comparing the effects of LTH in the fetal and adult periods on α-AR subtypes and PE-mediated Ca 2+ responses and contractions. To address this, we performed wire myography, Ca 2+ imaging, and mRNA analysis of pulmonary arteries from ewes and fetuses exposed to LTH or normoxia. Postnatal maturation depressed PE-mediated contractile responses. α 2 -AR activation contracted fetal vessels; however, this was suppressed by LTH. α 1A - and α 1B -AR subtypes contributed to arterial contractions in all groups. The α 1D -AR was also important to contractility in fetal normoxic vessels and LTH mitigated its function. Postnatal maturity increased the number of myocytes with PE-triggered Ca 2+ responses while LTH decreased the percentage of fetal myocytes reacting to PE. The difference between myocyte Ca 2+ responsiveness and vessel contractility suggests that fetal arteries are sensitized to changes in Ca 2+ . The results illustrate that α-adrenergic signaling and vascular function change during development and that LTH modifies adrenergic signaling. These changes may represent components in the etiology of pulmonary vascular disease and foretell the therapeutic potential of adrenergic receptor antagonists in the treatment of pulmonary hypertension.

Biomechanical and structural responses of the aorta to intermittent hypobaric hypoxia in a rat model

“…In contrast, no changes were observed in the vascular response to phenylephrine in-between groups. Finally, although sympathetic innervation is upregulated by hypoxia via receptor α- and β-adrenergic receptors (ARs) as shown in vascular circulation, in which adrenoceptors contribute to hypoxic vasoconstriction by hypoxia 47 , our results did not show significant difference in vasoconstriction by phenylephrine. It has been shown that there is a differential regulation in the expression of adrenoceptors in models of intermittent chronic hypoxia, in particular, the increase of the β2 isoform in relation to the β1 in smooth muscle cells of cardiac tissue 48 .…”

Prenatal hypoxia increases blood pressure in male rat offspring and affects their response to artificial light at night

“…PH can affect different regulatory areas in the brain and alter the expression of adrenergic receptors in the heart and arteries. [23][24][25] These changes can lead to a modified function of the autonomic nervous system and increase sympathetic nervous system activity. 8 Long-lasting PH can affect both the central and peripheral control mechanisms mediated by transcriptomic and epigenomic mechanisms.…”

“…8,15 The absence of differences in the BP response to norepinephrine administration between PH and control rats does not exclude the participation of the sympathetic nervous system in their different response to ALAN at the central level because peripherally administered norepinephrine is unable to penetrate the blood-brain barrier. 38 Furthermore, the expression of adrenergic receptors in the heart and blood vessels [23][24][25] can be different and should be further studied.…”

The newborn sheep translational model for pulmonary arterial hypertension of the neonate at high altitude

“…Increased wall thickness of small pulmonary arteries Llanos et al 30 Fetal/neonatal chronic hypoxia Increased pulmonary 5HT and PDE-5. Increased NO vasodilator capacity and wall thickness in small pulmonary arteries Parraguez et al 45 Fetal chronic hypoxia Long-and short-term exposure to high-altitude causes disturbances in maternal ovarian steroidogenesis and negatively affects embryo-fetal growth Moretta et al 47 Fetal chronic hypoxia Gestational hypoxia modulates pulmonary vasoconstriction potentially through upregulation of α1-AR.…”

“…2,17,21,31,34 The sheep has been used as a model that represents an animal not adapted to high altitude, such as the human species. 21,30,[42][43][44][45][46][47][48][49] Pregnant women and their unborn babies from several regions of the world are chronically exposed to the low-oxygen milieu of high-altitude mountains or plateaus. 21,50,51 Pregnancy at high altitude is clearly a potential burden for both mother and fetus.…”