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Pulmonary arterial hypertension (PAH) is a disease characterized by increased vasoconstriction and vascular remodeling. Pulmonary artery smooth muscle cells (PASMCs) highly express the transcription factor hypoxia-inducible factor-1α (HIF-1α), yet the role of PASMC HIF-1α in the development of PAH remains controversial. To study the role of SMC HIF-1α in the pulmonary vascular response to acute and chronic hypoxia, we used a gain-of-function strategy to stabilize HIF-1α in PASMC by generating mice lacking prolyl hydroxylase domain (PHD) 1 and 2 in SM22α-expressing cells. This strategy increased HIF-1α expression and transcriptional activity under conditions of normoxia and hypoxia. Acute hypoxia increased right ventricular systolic pressure (RVSP) in control, but not in SM22α-PHD1/2-/- mice. Chronic hypoxia increased RVSP and vascular remodeling more in control SM22α-PHD1/2+/+ than in SM22α-PHD1/2-/- mice. In vitro studies demonstrated increased contractility and myosin light chain phosphorylation in isolated PHD1/2+/+ compared with PHD1/2-/- PASMC under both normoxic and hypoxic conditions. After chronic hypoxia, there was more p27 and less vascular remodeling in SM22α-PHD1/2-/- compared with SM22α-PHD1/2+/+ mice. Hypoxia increased p27 in PASMC isolated from control patients, but not in cells from patients with idiopathic pulmonary arterial hypertension (IPAH). These findings highlight an SM22α-expressing cell-specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling. Modulating HIF-1α expression in PASMC may represent a promising preventative and therapeutic strategy for patients with PAH. NEW & NOTEWORTHY In a mouse model wherein hypoxia-inducible factor 1 alpha (HIF-1α) is stabilized in vascular smooth muscle cells, we found that HIF-1α regulates vasoconstriction by limiting phosphorylation of myosin light chain and regulates vascular remodeling through p27 induction. These findings highlight a cell-specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) has evolved considerably since its first description over 50 years ago. This review aims to provide a historical framework for conceptualizing BPD and a current understanding of the changing definition, epidemiology, pathophysiology, treatment, and outcomes of BPD. The transdisciplinary approach that led to the initial phenotypic description of BPD continues to hold promise today. Investigators are refining the definition of BPD in light of changes in clinical care and increasing survival rates of very preterm infants. Despite improvements in perinatal care the incidence of BPD continues to increase. There is growing recognition that antenatal risk factors play a key role in the development of BPD. Strategies designed to prevent or limit neonatal lung injury continue to evolve. Defining the phenotype of infants with BPD can meaningfully direct treatment. Infants with BPD benefit from an interdisciplinary approach to longitudinal care with a focus on growth and neurocognitive development. While the ultimate impact of BPD on long-term pulmonary morbidity remains an active area of investigation, current data indicate that most children and adolescents with a history of BPD have a quality of life comparable to that of other preterm infants. [ABSTRACT FROM AUTHOR]

Endothelin-1 (ET-1) increases pulmonary vascular tone through direct effects on pulmonary artery smooth muscle cells (PASMC) via membrane-bound ET-1 receptors. Circulating ET-1 contributes to vascular remodeling by promoting SMC proliferation and migration and inhibiting SMC apoptosis. Although endothelial cells (EC) are the primary source of ET-1, whether ET-1 produced by SMC modulates pulmonary vascular tone is unknown. Using transgenic mice created by crossbreeding SM22α-Cre mice with ET-1flox/flox mice to selectively delete ET-1 in SMC, we tested the hypothesis that PASMC ET-1 gene expression modulates the pulmonary vascular response to hypoxia. ET-1 gene deletion and selective activity of SM22α promoter-driven Cre recombinase were confirmed. Functional assays were performed under normoxic (21% O2) or hypoxic (5% O2) conditions using murine PASMC obtained from ET-1+/+ and ET-1-/- mic and in human PASMC (hPASMC) after silencing of ET-1 using siRNA. Under baseline conditions, there was no difference in right ventricular systolic pressure (RVSP) between SM22α-ET-1-/- and SM22α-ET-1+/+ (control) littermates. After exposure to hypoxia (10% O2, 21-24 days), RVSP was and vascular remodeling were less in SM22α-ET-1-/- mice compared with control littermates (P < 0.01). Loss of ET-1 decreased PASMC proliferation and migration and increased apoptosis under normoxic and hypoxic conditions. Exposure to selective ET-1 receptor antagonists had no effect on either the hypoxia-induced hPASMC proliferative or migratory response. SMC-specific ET-1 deletion attenuates hypoxia-induced increases in pulmonary vascular tone and structural remodeling. The observation that loss of ET-1 inhibited SMC proliferation, survival, and migration represents evidence that ET-1 derived from SMC plays a previously undescribed role in modulating the response of the pulmonary circulation to hypoxia. Thus PASMC ET-1 may modulate vascular tone independently of ET-1 produced by EC. [ABSTRACT FROM AUTHOR]

At birth, pulmonary vasodilation occurs concomitant with the onset of air-breathing life. Whether and how Rho kinase (ROCK) modulates the perinatal pulmonary vascular tone remains incompletely understood. To more fully characterize the separate and interactive effects of ROCK signaling, we hypothesized that ROCK has discrete effects on both pulmonary artery (PA): 1) endothelial cell (PAEC) nitric oxide (NO) production and contractile state; and 2) smooth muscle cell tone independent of endothelial NO synthase (eNOS) activity. To test these hypotheses, NO production and endothelial barrier function were determined in fetal PAEC under baseline hypoxia and following exposure to normoxia with and without treatment with Y-27632, a specific pharmacological inhibitor of ROCK. In acutely instrumented, late-gestation ovine fetuses, eNOS was inhibited by nitro-l-arginine infusion into the left PA (LPA). Subsequently, fetal lambs were mechanically ventilated (MV) with 100% oxygen in the absence (control period) and presence of Y-27632. In PAEC, treatment with Y-27632 had no effect on cytosolic calcium but did increase normoxia-induced NO production. Moreover, acute normoxia increased PAEC barrier function, an effect that was potentiated by Y-27632. In fetal lambs, MV during the control period had no effect on LPA flow. In contrast, MV after Y-27632 increased LPA flow and fetal arterial Po2 (PaO2) and decreased PA pressure. In conclusion, ROCK activity modulates vascular tone in the perinatal pulmonary circulation via combined effects on PAEC NO production, barrier function, and smooth muscle tone. ROCK inhibition may represent a novel treatment strategy for neonatal pulmonary vascular disease. [ABSTRACT FROM AUTHOR]

Oxygen causes perinatal pulmonary dilatation. Although fetal pulmonary artery smooth muscle cells (PA SMC) normally respond to an acute increase in oxygen (O2) tension with a decrease in cytosolic calcium ([Ca2+]i), an acute increase in O2 tension has no net effect on [Ca2+]i in PA SMC derived from lambs with chronic intrauterine pulmonary hypertension (PHTN). The present experimental series tests the hypothesis that an acute increase in O2 tension decreases capacitative calcium entry (CCE) in normal, but not hypertensive, fetal PA SMC. PA SMC were isolated from late-gestation fetal lambs after either ligation of the ductus arteriosus (PHTN) or sham (control) operation at 127 days gestation. PA SMC were isolated from the distal PA (≥4th generation) and maintained under hypoxic conditions (~25 Torr) in primary culture. After fura 2 loading, apparent [Ca2+]i in PA SMC was determined as the ratio of 340- to 380-nm fluorescence intensity. Under both hypoxic and normoxic conditions, cyclopiazonic acid (CPA) increased [Ca2+]i more in PI-ITN than in control PA SMC. CCE was determined in PA SMC under hypoxic and normoxic conditions, after superfusion with zero extracellular Ca2+ and intra- cellular store depletion with CPA, followed by superfusion with Ca2+-containing solution, in the presence of the voltage-operated calcium channel blockade. CCE was increased in PHTN compared with control PA SMC under conditions of both acute and sustained normoxia. Transient receptor potential channel gene expression was greater in control compared with PHTN PA SMC. PHTN may compromise perinatal pulmonary vasodilation, in part, by modulating PA SMC CCE. [ABSTRACT FROM AUTHOR]

Chronic intrauterine pulmonary hypertension compromises fetal pulmonary artery smooth muscle cell O[sub 2] sensing. Am J Physiol Lung Cell Mol Physiol 285: L1354-L1361, 2003. First published July 25, 2003; 10.1152/ajplung.00091.2003.—To test the hypothesis that chronic intrauterine pulmonary hypertension (PHTN) compromises pulmonary artery (PA) smooth muscle cell (SMC) O[sub 2] sensing, fluorescence microscopy was used to study the effect of an acute increase in Po[sub 2] on the cytosolic Ca[sup 2+] concentration ([Ca[sup 2+]][sub i]) of chronically hypoxic subconfluent monolayers of PA SMC in primary culture. PA SMCs were derived from fetal lambs with PHTN due to intrauterine ligation of the ductus arteriosus. Acute normoxia decreased [Ca[sup 2+]][sub i] in control but not PHTN PA SMC. In control PA SMC, [Ca[sup 2+]][sub i] increased after Ca[sup 2+]-sensitive (K[sub Ca]) and voltage-sensitive (K[sub v]) K[sup +] channel blockade and decreased after diltiazem treatment. In PHTN PA SMC, K[sub Ca] blockade had no effect, whereas Ky blockade and diltiazem increased [Ca[sup 2+]][sub i]. Inhibition of sarcoplasmic reticulum Ca[sup 2+] ATPase activity caused a greater increase in [Ca[sup 2+]][sub i] in controls compared with PHTN PA SMC. Conversely, ryanodine caused a greater increase of [Ca[sup 2+]][sub i] in PHTN compared with control PA SMC. K[sub Ca] channel mRNA is decreased and Ky channel mRNA is unchanged in PHTN PA SMC compared with controls. We conclude that PHTN compromises PA SMC O[sub 2] sensing, alters intracellular Ca[sup 2+] homeostasis, and changes the predominant ion channel that determines basal [Ca[sup 2+]][sub i] from K[sub Ca] to K[sub v]. [ABSTRACT FROM AUTHOR]

: BackgroundThe present study tests the hypothesis that therapy with inhaled nitric oxide (iNO) at the time of lung transplantation in patients undergoing bilateral single lung transplantation: (i) is safe; and (ii) does not increase either the duration of mechanical ventilation or the incidence of acute graft dysfunction.: MethodsWe conducted a prospective, non-randomized trial of iNO at 20 parts per million. The treatment group was comprised of 14 patients (10 females, 4 males) undergoing lung transplantation to address severe end-stage lung disease and pulmonary hypertension (mean pulmonary artery pressure > 30 mmHg). Clinical and histologic parameters were compared with 22 historical control subjects who were matched with the study population for age, diagnosis and disease severity (17 females, 5 males) and had undergone lung transplantation in the preceding 2-year time period. No significant differences were noted between the 2 study groups at baseline.: ResultsNo toxic effect of iNO treatment was evident. Although the incidence of acute graft dysfunction was the same in both groups, the occurrence of acute graft rejection in the initial 4 weeks after transplant was less frequent in the iNO group than in the control group (7% vs 32%, p = 0.05). Fifty percent of the treatment group, as compared with 22% of the control group, were discharged from the hospital within 2 weeks of the procedure (p = 0.05).: ConclusionsEarly initiation of iNO in lung transplant patients with pulmonary hypertension is safe and may decrease the incidence of acute graft rejection. We speculate that iNO may exert an immunomodulatory effect. J Heart Lung Transplant 2003. [Copyright &y& Elsevier]

Ca[sup 2+]-sensitive K[sup +] (K[sub Ca]) channels play an important role in mediating perinatal pulmonary vasodilation. We hypothesized that lung K[sub Ca] channel function may be decreased in persistent pulmonary hypertension of the newborn (PPHN). To test this hypothesis, pulmonary artery smooth muscle cells (PASMC) were isolated from fetal lambs with severe pulmonary hypertension induced by ligation of the ductus arteriosus in fetal lambs at 125-128 days gestation. Fetal lambs were killed after pulmonary hypertension had been maintained for at least 7 days. Age-matched, sham-operated animals were used as controls. PASMC K[sup +] currents and membrane potentials were recorded using amphotericin B-perforated patch-clamp techniques. The increase in whole cell current normally seen in response to normoxia was decreased (333.9 ± 63.6% in control vs. 133.1 ± 16.0% in hypertensive fetuses). The contribution of the K[sub Ca] channel to the whole cell current was diminished in hypertensive, compared with control, fetal PASMC. In PASMC from hypertensive fetuses, a change from hypoxia to normoxia caused no change in membrane potential compared with a -14.6 ± 2.8 mV decrease in membrane potential in PASMC from control animals. In PASMC from animals with pulmonary hypertension, 4-aminopyridine (4-AP) caused a larger depolarization than iberiotoxin, whereas in PASMC from control animals, iberiotexin caused a larger depolarization than 4-AP. These data confirm the hypothesis that the contribution of the K[sub Ca] channel to membrane potential and O[sub 2] sensitivity is decreased in an ovine model of PPHN, and this may contribute to the abnormal porinatal pulmonary vasoreactivity associated with PPHN. [ABSTRACT FROM AUTHOR]

Focuses on a study which discussed the role of chronic intrauterine pulmonary hypertension in calcium-sensitive potassium channel messenger RNA expression. Role of calcium-sensitive channels in perinatal pulmonary vasodilation; Materials and methods used; Results; Conclusions.

Pulmonary hypertension is associated with diverse cardiac, pulmonary, and systemic diseases in neonates, infants, and older children and contributes to significant morbidity and mortality. However, current approaches to caring for pediatric patients with pulmonary hypertension have been limited by the lack of consensus guidelines from experts in the field. In a joint effort from the American Heart Association and American Thoracic Society, a panel of experienced clinicians and clinician-scientists was assembled to review the current literature and to make recommendations on the diagnosis, evaluation, and treatment of pediatric pulmonary hypertension. This publication presents the results of extensive literature reviews, discussions, and formal scoring of recommendations for the care of children with pulmonary hypertension. [ABSTRACT FROM AUTHOR]