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1 BHF Laboratories, University College London, London, United Kingdom; Vascular Developmental Biology, Institute of Child Health UCL, London, United Kingdom
2 Kennedy Institute of Rheumatology, Imperial College, London, United Kingdom
3 Vascular Developmental Biology, Institute of Child Health UCL, London, United Kingdom
* To whom correspondence should be addressed. E-mail: B.Wojciak-Stothard{at}ucl.ac.uk.
Hypoxia is a common cause of pulmonary hypertension in the newborn (PPHN), a condition associated with endothelial dysfunction and abnormal pulmonary vascular remodelling. The GTPase RhoA has been implicated in the pathogenesis of PPHN but its contribution to endothelial remodelling and function is not known. We studied pulmonary artery endothelial cells (PAECs) taken from piglets with chronic hypoxia-induced pulmonary hypertension and from healthy animals and analysed the roles of Rho GTPases in the regulation of endothelial phenotype and function in basal normoxic conditions, acute hypoxia and reoxygenation. The activities of RhoA, Rac1 and Cdc42 were correlated with changes in the endothelial cytoskeleton, adherens junctions, permeability, reactive oxygen species (ROS) production, VEGF levels and the activity of transcription factors HIF-1
and NF
B. Adenoviral gene transfer was used to express dominant negative GTPases, kinase dead p21-activated kinase (PAK-1) and constitutively activated Rac1 in cells. PAECs from pulmonary hypertensive piglets had a stable abnormal phenotype with a sustained reduction in Rac1 activity and an increase in RhoA activity which correlated with an increase in actin stress fibre formation, increased permeability and a decrease in VEGF and ROS production. Cells from pulmonary hypertensive animals were still able to respond to acute hypoxia. They also showed high activities of hypoxia inducible factor 1 alpha (HIF1 ) and NFB, likely to result from changes in the activities of Rho GTPases. Activation of Rac1 and its effector PAK-1 as well as inhibition of RhoA restored the abnormal phenotype and permeability of hypertensive PAECs to normal.
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