Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Abstract

-Bradykinin-induced activation of the pulmonary endothelium triggers nitric oxide production and other signals that cause vasorelaxation, including stimulation of largeconductance Ca 2ϩ -activated K ϩ (BKCa) channels in myocytes that hyperpolarize the plasma membrane and decrease intracellular Ca 2ϩ . Intrauterine chronic hypoxia (CH) may reduce vasorelaxation in the fetal-to-newborn transition and contribute to pulmonary hypertension of the newborn. Thus we examined the effects of maturation and CH on the role of BKCa channels during bradykinin-induced vasorelaxation by examining endothelial Ca 2ϩ signals, wire myography, and Western immunoblots on pulmonary arteries isolated from near-term fetal (ϳ140 days gestation) and newborn, 10-to 20-day-old, sheep that lived in normoxia at 700 m or in CH at high altitude (3,801 m) for Ͼ100 days. CH enhanced bradykinin-induced relaxation of fetal vessels but decreased relaxation in newborns. Endothelial Ca 2ϩ responses decreased with maturation but increased with CH. Bradykinin-dependent relaxation was sensitive to 100 M nitro-L-arginine methyl ester or 10 M 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, supporting roles for endothelial nitric oxide synthase and soluble guanylate cyclase activation. Indomethacin blocked relaxation in CH vessels, suggesting upregulation of PLA2 pathways. BKCa channel inhibition with 1 mM tetraethylammonium reduced bradykinin-induced vasorelaxation in the normoxic newborn and fetal CH vessels. Maturation reduced whole cell BKCa channel ␣1-subunit expression but increased ␤1-subunit expression. These results suggest that CH amplifies the contribution of BKCa channels to bradykinin-induced vasorelaxation in fetal sheep but stunts further development of this vasodilatory pathway in newborns. This involves complex changes in multiple components of the bradykinin-signaling axes. potassium channels; sheep; pulmonary artery; contractility; maturation; hypoxia REGULATION OF SMOOTH MUSCLE tone in pulmonary arteries during development is a delicate balance of vasoconstrictive and vasorelaxant pathways. Endothelial cells play a crucial role in determining the overall level of vasorelaxation (39, 67), and endothelium-dependent relaxation is partially mediated through bradykinin stimulation (31). Bradykinin is a potent vasodilator that is important in the fetal pulmonary circulation, as well as during inflammation, and its relationship to pulmonary hypertension has been explored (5, 31, 83).Endothelial bradykinin receptor activation induces vasorelaxation through modulation of several different intracellular signaling pathways that are largely dependent on a rise of endothelial intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (67). The most widely studied pathway is bradykinin-induced activation of endothelial nitric oxide (NO) synthase (eNOS), an enzyme that generates NO (64). NO acts on nearby smooth muscle cells to cause downstream stimulation of soluble guanylate cyclase (sGC) pathways that leads to vasorelaxation (3,45). Previous studies have shown that regulatio...

Changes in the nitric oxide pathway of the pulmonary vasculature after exposure to hypoxia in swine model of neonatal pulmonary vascular disease

“…These data are consistent with a study showing that perinatal hypoxia results in an impaired vasodilator response to bradykinin in isolated pulmonary small arteries of lambs (Blum‐Johnston et al. ). We have previously shown that pulmonary vasodilation to bradykinin is largely NO‐dependent (de Wijs‐Meijler et al.…”

“…; Blum‐Johnston et al. ), and we have previously shown that neonatal hypoxia‐induced pulmonary vascular alterations persist for several weeks following re‐exposure to normoxia (de Wijs‐Meijler et al. 2017c), we investigated the functionality of different parts of this pathway in our model of neonatal hypoxia‐induced PH.…”

“…Thus, perinatal hypoxia in lambs did not affect the contribution of NO to bradykinin‐induced dilatation (Blum‐Johnston et al. ).…”

“…However, their contribution to bradykinin‐induced vasodilatation in vitro following perinatal hypoxia was reduced (Blum‐Johnston et al. ). Altogether, evidence from the literature as well as the present study suggests that the impaired endothelium‐dependent vasodilatation in piglets with hypoxia‐induced PH in the first 3 weeks after re‐exposure to normoxia is due to a reduced responsiveness to NO, probably caused by altered sensitivity and/or activity of sGC, resulting is an impaired cGMP production, which may (partially) be compensated by an increased expression of BK Ca channels.…”

Nitric Oxide–Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries

“…The biophysical properties, signaling targets, and endogenous regulators of TRPV4 sparklets in small PAs remain unknown. Endothelium‐derived nitric oxide (NO) is thought to be the predominant vasodilator in the pulmonary circulation 8, 9, 10, 11, 12. Increase in global Ca 2+ has long been associated with activation of endothelial nitric oxide synthase (eNOS).…”