Serotonin (5‐HT) signaling plays important roles in pulmonary vascular contractility and development. Several studies illustrate that 5‐HT mediated pulmonary arterial (PA) contractility adapts with development in sheep and rat and in response to chronic hypoxic (CH) stress in the rat. Our studies show that 5‐HT induced Ca2+ elevations in fewer PA myocytes from fetal relative to adult sheep suggesting there may be increases in receptor expression associated with maturation. Using wire myography approaches, the present study tested the hypothesis that CH and maturation increase the potency as well as efficacy of 5‐HT‐mediated PA contractility in sheep. The results show the EC50 to 5‐HT was unchanged with maturation in PA from normoxic sheep. However, the potency to 5‐HT was reduced with CH in fetus and increased in adult. The tension developed by 10 μM 5‐HT increased with maturation but not CH and no differences were observed when normalized to the tension due to 125 mM KCl. Moreover, in all groups the contractility to 1 μM 5‐HT was completely abolished by 100 nM Ketanserin, a selective 5‐HT2A antagonist. In conclusion, based on this and our previous studies the changes in 5‐HT efficacy and potency with maturation and CH are most likely due to altered receptor number, second messenger coupling or phenotypic alterations in PA myocyte function. (Support from NIH, Sigma Xi, and UM)
Serotonin (5‐HT) regulates pulmonary arterial (PA) contractility through calcium and kinase dependent signaling pathways and this activity may change during postnatal development as well as in response to chronic hypoxia (CH). Although 5‐HT activates numerous kinase pathways, protein kinase C (PKC), Rho kinase, and extracellular regulated kinase (ERK) are important to arterial reactivity. Among these, Rho kinase is upregulated by CH in PA of fetal sheep and adult rat. The hypothesis that there is preferential increase in Rho kinase over PKC and ERK pathways in response to CH and maturation was therefore tested by measuring contractility responses in PA rings isolated from CH fetal and adult sheep. PA rings were stimulated with 10 μM 5‐HT and comparative analyses of the kinase pathways made in the absence and then presence of inhibitors of PKC (1 μM BIM I), RhoA (10 μM Y 27632), and ERK (10 μM U0126). All three kinase pathways contributed equally to 5‐HT elicited contractility in adult whereas RhoA was augmented in fetus, while PKC and ERK had negligible roles. In conclusion, the studies provide evidence for selective changes in kinase signaling pathways that may be due to either maturation or CH. This study supports a role for altered kinase signaling in the development of pulmonary arterial disease and illustrates the therapeutic importance of RhoA pathways in hypertension of the newborn. (Support from UM, NIH and Sigma Xi)
Serotonin (5‐HT) regulates pulmonary arterial (PA) contractility through Ca2+ and kinase dependent signaling pathways and many reports indicate these pathways are altered by chronic hypoxia (CH). Among the many kinase pathways activated by 5‐HT, protein kinase C (PKC), Rho kinase, and extracellular regulated kinase (ERK) are important to arterial reactivity. As we have found CH causes selective reductions in Ca2+‐dependent PA contractility in fetus and adult, we used wire‐myography and Western immunoblot techniques to test the hypothesis that CH upregulates kinase‐dependent contractility. PA rings were stimulated with 10 μM 5‐HT and comparative analyses of the kinase pathways were made in the absence and then presence of inhibitors of PKC (1 μM BIM I), RhoA (10 μM Y 27632), and ERK (10 μM U0126). CH did not affect the role for PKC in adult, which did not have an appreciable role in fetus. CH restricted the influence of Rho kinase in fetus and adult, and may cause ERK to become a negative regulator of contractility in adult. CH upregulated ROCK‐II in adult but did not influence the relative expression of PKCα, ERK‐I, ERK‐II, or ROCK‐I in either adult or fetus. In conclusion, maturation and CH cause complex changes in PKC, ERK and Rho kinase‐dependent contractility, which likely integrates with alterations in Ca2+‐signaling to regulate vascular reactivity. Support from NIH, UM, LLUMC, and Sigma Xi.
Muscarinic acetylcholine (ACh) receptor (mAChR) activation relaxes arteries through endothelium‐dependent NO signaling pathways and endothelium removal from most systemic arteries alleviates ACh mediated relaxation. However, Ach induces “paradoxical” contractility in endothelium disrupted pulmonary arteries (PA), through mAChR activation in multiple species including human. Chronic hypoxia (CH) disrupts vascular endothelium, producing loss of endothelium‐dependent PA relaxation. Given the intimacy between endothelial and myocyte function the hypothesis that CH reduces ACh‐dependent PA contractility was tested by performing wire‐myography of endothelium‐denuded PA rings from normoxic fetal and adult animals. The data show that Ach (100 μM) contracted arteries pre‐contracted with 125 mM KCl and this contractility was reduced by CH in adult PA and ablated in fetus. In CH adult, the mAChR agonist carbachol (CCh, 10 μM) caused contraction while 1 μM atropine (mAChR antagonist) blocked Ach and CCh contractility. Consistent with mAChR activation, In situ confocal microscopy approaches show Ach caused cytosolic Ca2+ increases in PA myocytes of CH adult. In conclusion, this study provides evidence for CH induced loss of mAChR PA contractility, a process that likely helps match ventilation to perfusion, especially as ACh causes bronchoconstriction. (Support from NIH, NSF and UM)
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