Decreased Kv1.5 expression in intrauterine growth retardation rats with exaggerated pulmonary hypertension

Abstract

Chronic hypoxia pulmonary hypertension (CH-PHT) in adulthood is likely to be of fetal origin following intrauterine growth retardation (IUGR). Oxygen (O2)-sensitive voltage-gated potassium channels (Kv channels) in resistance pulmonary artery smooth muscle cells (PASMCs) play an important role in scaling pulmonary artery (PA) pressure. Expression and functional changes of Kv channels are determined, in part, by embryonic development. We hypothesized that O2-sensitive Kv channels play an important role in exaggerated CH-PHT following IUGR. We established a rat model of IUGR by restricting maternal food during the entire pregnancy and exposed IUGR rats and their agematched controls aged 12 wk to hypoxia for 2 wk. We found that hypoxia exposure significantly induced increased PA pressure and thicker smooth muscle layer in the IUGR group relative to controls. We compared the constriction of the resistance PA to inhibitors of K ϩ channels, 4-aminopyridine (4-AP), tetraethylammonium, and BaCl2. Despite the thickness of the smooth muscle layer, the constriction to 4-AP was significantly reduced in the IUGR group exposed to hypoxia. Consistent with these changes in pulmonary vascular reactivity, 2 wk of hypoxia induced weaker 4-AP-sensitive Kv currents in a single IUGR PASMC. Moreover, after 2 wk of hypoxia, Kv1.5 expression in resistance PAs decreased significantly in the IUGR group. Overexpression of Kv1.5 in cultured PASMCs could offset hypoxia-induced cell proliferation and hypoxia-inhibited Kv currents in the IUGR group. These results suggest that the inhibited expression of Kv1.5 in PASMCs contribute to the development of exaggerated CH-PHT in IUGR rats during adulthood. chronic hypoxic pulmonary hypertension; intrauterine growth retardation; voltage-gated potassium channel; pulmonary artery smooth muscle cell RECENTLY, INTRAUTERINE GROWTH RETARDATION (IUGR) has been considered to be associated with the fetal origin of adult disease (4). IUGR is defined as having a birth weight below the 10th percentile of the corresponding gestational age (25). Several studies have demonstrated that IUGR predicts the risk of developing various adult diseases, including obesity, Type 2 diabetes, and hypertension (12, 33). Its biological risk factors include intrauterine malnutrition and intrauterine hypoxia. Intrauterine hypoxia may also have a persistent effect on the infant pulmonary vasculature, which, when activated in adult life, predisposes to a pathological response (32). Similar to that in our recent study, exaggerated pulmonary hypertension (PHT) was observed because of exposure to chronic hypoxia in adult IUGR male rats. Additionally, intrauterine malnutrition plays an important role during this process (39). Another study showed that PHT of offspring in adulthood is associated with maternal undernutrition during pregnancy, although the offspring do not exhibit low birth weight (30). Moreover, maternal protein restriction during pregnancy limits fetal pulmonary development, a finding that may increase the susceptibility ...

In Utero Origins of Hypertension: Mechanisms and Targets for Therapy

“…The primary activator of BK Ca is epoxyeicoatrienoic acid (EET); however, changes in the production of EET from arachidonic acid have not been addressed in models of developmental programming. The involvement of other potassium channels, such as the voltage-gated potassium channel (K V ), was reduced in the pulmonary arteries from rat offspring of nutrient restricted dams, while the K Ca and inward-rectifying potassium channels (K IR ) were unaltered (240). In other studies, EDH contribution to vasodilation was maintained in rat offspring of hypoxic dams while the involvement of myoendothelial gap junctions increased in females but not males (265,266).…”

“…An increased occurrence of aortic internal elastic lamina defects was also observed in offspring of bilateral uterine artery ligation rats (299). Vascular remodeling has been observed in the pulmonary arteries, where maternal nutrient restriction led to increased smooth muscle thickness following acute (240) or chronic (375,445) exposure of the offspring to hypoxia. Furthermore, the mesenteric arcade smooth muscle content was increased in a maternal undernutrition model (200).…”

Recent advances in the mechanisms of lung alveolarization and the pathogenesis of bronchopulmonary dysplasia

“…Additionally, antagonism of PDE5 with sildenafil promoted pulmonary vascular development and alveolarization, ostensibly via activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt/mammalian target of rapamycin pathway and enhanced HIF-1␣ and HIF-2␣ activity (270). Other candidate regulators of lung vessel cell behavior have also been identified in vitro, including heat-shock protein 70 (5), the oxygen-sensitive voltage-gated potassium channel Kv1.5 (202), and AMPK (330); however, a role for these molecules in pulmonary vascular development awaits clarification.…”

Hypoxia-Dependent Reactive Oxygen Species Signaling in the Pulmonary Circulation: Focus on Ion Channels

“…While acute hypoxia acts via inhibition of Kv channel activity, during chronic hypoxia K + channel density and Kv channel protein expression (Kv1.5 and Kv2.1) is decreased, although a Kv current is still detectable (124). However, both induction and repression of Kv channel subunit expression under chronic hypoxia has been described (44, 61,91,147). Patch clamp studies showed that the hypoxic inhibition of the Kv current in PASMC is unchanged even after 2 days of ambient hypoxia, when HPV is already lost (169).…”