Pulmonary hypertension (PH) is a devastating pulmonary vascular disease characterized by aberrant muscularization of the normally nonmuscularized distal pulmonary arterioles. The expression of the transcription factor, Twist1, increases in the lungs of patients with pulmonary arterial hypertension. However, the mechanisms by which Twist1 controls the pathogenesis of PH remain unclear. It is becoming clear that endothelial-to-mesenchymal transition (EndMT) contributes to various vascular pathologies, including PH; Twist1 is known to mediate EndMT. In this report, we demonstrate that Twist1 overexpression increases transforming growth factor (TGF) β receptor2 (TGF-βR2) expression and Smad2 phosphorylation, and induces EndMT in cultured human pulmonary arterial endothelial (HPAE) cells, whereas a mutant construct of Twist1 at the serine 42 residue (Twist1S42A) fails to induce EndMT. We also implanted fibrin gel supplemented with HPAE cells on the mouse lung, and found that these HPAE cells form vascular structures and that Twist1-overexpressing HPAE cells undergo EndMT in the gel, whereas Twist1S42A-overexpressing cells do not. Furthermore, hypoxia-induced EndMT is inhibited in endothelial cells overexpressing Twist1S42A mutant construct in vitro. Hypoxia-induced accumulation of α-smooth muscle actin-positive cells in the pulmonary arterioles is attenuated in Tie2-specific Twist1 conditional knockout mice in vivo. These findings suggest that Twist1 serine 42 phosphorylation plays a key role in EndMT through TGF-β signaling and that modulation of Twist1 phosphorylation could be an effective strategy for managing PH.
Objectives-We hypothesized that inhaled nitric oxide (iNO) would not decrease death or neurodevelopmental impairment (NDI) in infants enrolled in the NICHD Preemie iNO Trial (PiNO) trial, nor improve neurodevelopmental outcomes among the follow-up group.Study design-Infants <34 weeks, <1500 g with severe respiratory failure were enrolled in the multicenter, randomized, controlled trial. NDI at 18-22 months corrected age was defined as: moderate to severe cerebral palsy (CP), MDI or PDI score<70, blindness, or deafness.Results-Of 420 patients enrolled, 109 receiving iNO (52%) and 98 receiving placebo (47%) died. The follow-up rate among survivors was 90%. iNO did not reduce death or NDI (78% vs. 73%; [RR (95%CI) 1.07 (0.95-1.19)], or NDI or MDI<70 among the follow-up group. Moderate-severe CP was slightly higher with iNO [2.41 (1.01-5.75)], as was death or CP among infants ≤1000 g BW [1.22 (1.05-1.43)].Conclusions-In this extremely ill cohort, iNO did not reduce death or NDI, or improve neurodevelopmental outcomes. Routine iNO use among premature infants should be limited to research settings until further data are available. Keywords premature; nitric oxide; cerebral palsy; Bayley Scales of Infant Development; extremely low birth weight (ELBW); very low birth weight (VLBW); neurodevelopmentalThe prognosis for survival of the most vulnerable preterm infants has improved dramatically due to advances in perinatal and neonatal care (1,2), but their neurodevelopmental outcomes do not appear to have benefited similarly. Cerebral palsy (CP) rates among extremely preterm and extremely low birth weight (ELBW) infants have been unchanged over time (3,4 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. worsening (5-7), unchanged (8), or mildly improved (4). Therefore, there is a substantial impetus to find interventions that improve neurodevelopmental outcomes. NIH Public AccessResults of a single-center, randomized controlled trial among premature infants found that treatment with inhaled nitric oxide (iNO) significantly reduced death or chronic lung disease (9), and disability or developmental delay at 2-years of age (10). A recent multicenter study of moderately ill, preterm infants treated with iNO beginning at <48 hours showed a reduced rate of death or bronchopulmonary (BPD) only in subgroup analysis of infants with birth weight 1000-1250 grams (11). Another multicenter study of preterm infants with more established lung disease treated with iNO beginning after 7 days of age showed an increased rate of survival without BPD (12). In the NICHD Neonatal Research Network, we...
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