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 α1-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 Ca2+ responses and contractions. To address this, we performed wire myography, Ca2+ imaging, and mRNA analysis of pulmonary arteries from ewes and fetuses exposed to LTH or normoxia. Postnatal maturation depressed PE-mediated contractile responses. α2-AR activation contracted fetal vessels; however, this was suppressed by LTH. α1A- and α1B-AR subtypes contributed to arterial contractions in all groups. The α1D-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 Ca2+ responses while LTH decreased the percentage of fetal myocytes reacting to PE. The difference between myocyte Ca2+ responsiveness and vessel contractility suggests that fetal arteries are sensitized to changes in Ca2+. 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.
Highlights
The pulmonary circulation is regulated to optimize respiratory gas exchange
The present study provides new information systematically comparing the effects of long-term hypoxia (LTH) in the fetal and adult periods on the functional changes for the role of α1- and α2-adrenergic receptors in the pulmonary vasculature
The contractile properties produced by adrenergic stimulation are complex and take place in the context of changing vessel behavior due to long-term hypoxia (LTH) exposure
Summary
The pulmonary circulation is regulated to optimize respiratory gas exchange. Various factors affect pulmonary vascular reactivity, including neural, hormonal, inflammatory, and local mediators. Autonomic innervation of the pulmonary vasculature has been documented in various mammals there is significant variation in the distribution of the nerves (Barnes and Liu, 1995). Considerable evidence indicates there is a greater density of autonomic nerve fibers in larger vessels and vascular branching points (Daly and Hebb, 1966). The functional significance of sympathetic innervation of the human lung is not well understood both α- and β-adrenergic receptors (ARs) are expressed in the pulmonary vascular bed. Α-AR function predominates, in the fetal circulation with a higher basal vasomotor tone and greater reactivity to α-adrenergic stimulation (Mandel and Taichman, 2006). Long-term hypoxia (LTH) results in upregulation of α1-AR gene transcription (Salvi, 1999)
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