1 Decreased Kv 1 . 5 expression in intrauterine growth retardation rats with 2 exaggerated pulmonary hypertension 3

18 Chronic hypoxia pulmonary hypertension (CH-PHT) in adulthood is likely to be of fetal 19 origin following intrauterine growth retardation (IUGR). Oxygen (O2)-sensitive voltage20 gated potassium channels (Kv channels) in resistance pulmonary artery smooth muscle 21 cells (PASMCs) play an important role in scaling pulmonary artery pressure. Expression 22 and functional changes of Kv channels are determined, in part, by embryonic 23 development. We hypothesized that O2-sensitive Kv channels play an important role in 24 exaggerated CH-PHT following IUGR. We established a rat model of IUGR by restricting 25 maternal food during the entire pregnancy and exposed IUGR rats and their age26 matched controls aged12 weeks to hypoxia for 2 weeks. We found that hypoxia exposure 27 significantly induced increased pulmonary artery (PA) pressure and thicker smooth 28 muscle layer in the IUGR group relative to controls. We compared the constriction of the 29 resistance PA to inhibitors of K channels, 4-aminopyridine (4-AP), tetraethylammonium 30 (TEA), and barium chloride (BaCl2). Despite the thickness of the smooth muscle layer, 31 the constriction to 4-AP was significantly reduced in the IUGR group exposed to hypoxia. 32 Consistent with these changes in pulmonary vascular reactivity, 2 weeks of hypoxia 33 induced weaker 4-AP-sensitive Kv currents in a single IUGR PASMC. Moreover, after 2 34 weeks of hypoxia, Kv1.5 expression in resistance PAs decreased significantly in the 35 IUGR group. Overexpression of Kv1.5 in cultured PASMCs could offset hypoxia-induced 36 cell proliferation and hypoxia-inhibited Kv currents in the IUGR group. These results 37 suggest that the inhibited expression of Kv1.5 in PASMCs contribute to the development 38 of exaggerated CH-PHT in IUGR rats during adulthood. 39