Hypoxia and Rho/Rho-kinase signaling: Lung development versus hypoxic pulmonary hypertension

Abstract

Intracellular signaling via the small GTP-binding protein RhoA and its downstream effector Rho-kinase plays a role in regulating diverse cellular functions, including cell contraction, migration, gene expression, proliferation, and differentiation. Rho/Rho-kinase signaling has an obligatory role in embryonic cardiac development, and low-level chemical activation of Rho promotes branching morphogenesis in fetal lung explants. Gebb has found that hypoxia markedly augments branching morphogenesis in fetal rat lung explants, and our preliminary results suggest this is associated with activation of RhoA. Whereas hypoxia-induced activation of Rho/Rho-kinase may promote fetal lung development, other evidence indicates it has adverse effects in the lungs of neonates and adults. When exposed at birth to the mild hypoxia of Denver's altitude (5,280 ft), the neonatal fawn-hooded rat (FHR) develops severe pulmonary hypertension (PH) associated with impaired lung alveolarization and vascularization. We have observed that administration via the drinking water of the Rho-kinase inhibitor fasudil to the nursing, Denver FHR mother for the first 2 to 3 weeks, and then directly to the Denver FHR pups for the next 7 to 8 weeks, ameliorates the lung dysplasia and PH. The adult Sprague-Dawley rat develops PH when exposed for 3 to 4 wk to a simulated altitude of 17,000 ft. We have found that this hypoxic PH is associated with activation of pulmonary artery Rho/Rho-kinase and is almost completely reversed by acute intravenous administration of the Rho-kinase inhibitor Y-27632. In addition, chronic in vivo treatment with Y-27632 reduces development of the hypoxic PH. In summary, hypoxic activation of Rho/Rho-kinase signaling may be important for fetal lung morphogenesis, but continued activation of this pathway in the neonate impairs postnatal lung development and re-activation in the adult contributes to development of PH.