Contributions of PKC, RhoA and ERK signaling to serotonergic contractility of pulmonary arteries from chronic hypoxic fetal and adult sheep

Abstract

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)