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Kurt R Stenmark - One of the best experts on this subject based on the ideXlab platform.
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myocyte cytoskeletal disorganization and right heart failure in hypoxia induced Neonatal Pulmonary Hypertension
American Journal of Physiology-heart and Circulatory Physiology, 2000Co-Authors: Matthew S Lemler, Roger D Bies, Maria G Frid, Amornrate Sastravaha, Lawrence S Zisman, Teresa J Bohlmeyer, Martin A Gerdes, J T Reeves, Kurt R StenmarkAbstract:Previous studies have demonstrated that environmentally or genetically induced changes in the intracellular proteins that compose the cytoskeleton can contribute to heart failure. Because Neonatal right ventricular myocytes are immature and are in the process of significant cytoskeletal change, we hypothesized that they may be particularly susceptible to pressure stress. Newborn calves exposed to hypobaric hypoxia (barometric pressure = 430 mmHg) for 14 days developed severe Pulmonary Hypertension (Pulmonary arterial pressure = 101 ± 6 vs. 27 ± 1 mmHg) and right heart failure compared with age-matched controls. Light microscopy showed partial loss of myocardial striations in the failing Neonatal right but not left ventricles and in neither ventricle of adolescent cattle dying of altitude-induced right heart failure. In Neonatal calves, immunohistochemical analysis of the cytoskeletal proteins (vinculin, metavinculin, desmin, vimentin, and cadherin) showed selectively, within the failing right ventricles, patchy areas characterized by loss and disorganization of costameres and intercalated discs. Within myocytes from the failing ventricles, vinculin and desmin were observed to redistribute diffusely within the cytosol, metavinculin appeared in disorganized clumps, and vimentin immunoreactivity was markedly decreased. Western blot analysis of the failing right ventricular myocardium showed, compared with control, vinculin and desmin to be little changed in total content but redistributed from insoluble (structural) to soluble (cytosolic) fractions; metavinculin total content was markedly decreased, tubulin content increased, particularly in the structural fraction, and cadherin total content and distribution were unchanged. We conclude that hypoxic Pulmonary hypertensive-induced Neonatal right ventricular failure is associated with disorganization of the cytoskeletal architecture.
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persistent Pulmonary Hypertension of the newborn
American Journal of Respiratory and Critical Care Medicine, 1995Co-Authors: Frederick C Morin, Kurt R StenmarkAbstract:Pulmonary Hypertension in humans is characterized by significant increases in cell proliferation and extracellular matrix protein production in Pulmonary vascular wall cells [1]. The fibroproliferative response in Neonatal Pulmonary Hypertension is particularly exuberant compared with changes observed in adults, yet the reasons for these age-related differences remain, for the most part, obscure (Fig. 1).
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persistence re expression and induction of Pulmonary arterial fibronectin tropoelastin and type i procollagen mrna expression in Neonatal hypoxic Pulmonary Hypertension
American Journal of Pathology, 1994Co-Authors: Anthony G Durmowicz, William C Parks, Dallas M Hyde, Robert P Mecham, Kurt R StenmarkAbstract:Changes in the structure and function of muscular Pulmonary arteries are crucial for normal adaptation to extrauterine life and rapid changes in matrix protein gene expression are likely necessary for this adaptation. We hypothesized that pathological stimuli imposed at the time of birth would alter developmental changes in matrix protein gene expression thereby affecting the normal post-uterine changes in Pulmonary hemodynamics. We used in situ hybridization to examine the normal developmental expression of three extracellular matrix protein mRNAs, fibronectin, tropoelastin, and alpha 1 (I) procollagen, in muscular Pulmonary arteries of both fetal and Neonatal calves and assessed the impact of severe hypoxia-induced Pulmonary Hypertension on their expression. Morphometric techniques were used to assess whether changes in matrix protein mRNA levels were related to changes in matrix fiber accumulation. Exposure to chronic hypoxia postnatally resulted in the persistence, reexpression, and induction of fibronectin, tropoelastin, and alpha 1 (I) procollagen mRNAs, respectively, in muscular Pulmonary arteries. In each case the hybridization signal was localized primarily to the adventitial layer of the vessel. Morphometric analysis showed that the increased hybridization signals seen correlated with an increase in both vascular elastin and collagen fiber volumes in the adventitial layer. We conclude that the change in expression of matrix genes in the Pulmonary artery wall during exposure to chronic hypoxia is an important adaptive response to changes in hemodynamic factors and/or oxygen tension. The unchecked increase in matrix protein expression seen likely contributes to the pathological Pulmonary arterial structural remodeling and loss of vasoreactivity that occurs during the development of severe Neonatal Pulmonary Hypertension.
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persistence of the fetal pattern of tropoelastin gene expression in severe Neonatal bovine Pulmonary Hypertension
Journal of Clinical Investigation, 1994Co-Authors: Kurt R Stenmark, Anthony G Durmowicz, Robert P Mecham, Jill D Roby, William C ParksAbstract:Neonatal hypoxic Pulmonary Hypertension causes increases and spatial changes in tropoelastin expression in Pulmonary arteries. However, it is not clear if this is due to recruitment of quiescent smooth muscle cells (SMC) into an elastin-producing phenotype or persistence ofthe fetal pattern oftropoelastin gene expression. We evaluated the distribution and relative concentration of tropoelastin mRNA in intralobar Pulmonary arteries from late gestation fetuses and in animals exposed to hypobaric hypoxia (430 mmHg) from birth for 1, 3, 7, or 14 d, as well as in age-matched and adult room air-breathing controls. In situ hybridization demonstrated that tropoelastin mRNA was distributed throughout the entire radius ofthe Pulmonary vessel wall in the fetus and newborn calf. By 15 d of age, only cells in the inner third of the media expressed tropoelastin mRNA, and by adulthood no tropoelastin mRNA was detected in the vessel wall. These findings demonstrated that tropoelastin expression shuts off in a spatially specific pattern, moving from the abluminal to the luminal side of the medial in the Neonatal Pulmonary artery when pressures and resistance are falling. In the aorta of 15-d-old calves, tropoelastin mRNA expression was seen equally throughout the media, indicating tissue-specific regulation of elastin in the Neonatal period. In contrast, intralobar Pulmonary arteries from calves exposed to hypoxia, which prevented the normal postnatal decline in Pulmonary artery pressure, maintained the fetal pattern and levels of tropoelastin mRNA expression at all time points. Thus, rather than causing a recruitment ofSMC into an elastin-producing phenotype, Neonatal Pulmonary Hypertension caused a persistence of the fetal pattern of tropoelastin expression in medial SMC. Cell-free translation showed that the same tropoelastin isoforms were made by mRNA from control and hypertensive calves and, unlike the ligamentum nuchae, did not change during the transition from fetal to Neonatal life. We conclude that Pulmonary Hypertension in the neonate perturbs the normal postpartum repression of tropoelastin expression resulting in a persistence of the fetal spacial and isoform patterns of tropoelastin gene expression. (J. Clin. Invest. 1994.
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progressive loss of vasodilator responsive component of Pulmonary Hypertension in Neonatal calves exposed to 4 570 m
American Journal of Physiology-heart and Circulatory Physiology, 1993Co-Authors: Anthony G Durmowicz, E C Orton, Kurt R StenmarkAbstract:Severe Neonatal Pulmonary Hypertension (PH) may have both reversible (vasoconstrictive) and “fixed” (vasodilator unresponsive) components. To assess when and to what degree vasodilator unresponsive...
Robin H Steinhorn - One of the best experts on this subject based on the ideXlab platform.
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advances in Neonatal Pulmonary Hypertension
Neonatology, 2016Co-Authors: Robin H SteinhornAbstract:Persistent Pulmonary Hypertension of the newborn (PPHN) is a surprisingly common event in the Neonatal intensive care unit, and affects both term and preterm infants. Recent studies have begun to elucidate the maternal, fetal and genetic risk factors that trigger PPHN. There have been numerous therapeutic advances over the last decade. It is now appreciated that oxygen supplementation, particularly for the goal of Pulmonary vasodilation, needs to be approached as a therapy that has risks and benefits. Administration of surfactant or inhaled nitric oxide (iNO) therapy at a lower acuity of illness can decrease the risk of extracorporeal membrane oxygenation/death, progression of disease and duration of hospital stay. Milrinone may have specific benefits as an 'inodilator', as prolonged exposure to iNO plus oxygen may activate phosphodiesterase (PDE) 3A. Additionally, sildenafil and hydrocortisone may benefit infants exposed to hyperoxia and oxidative stress. Continued investigation is likely to reveal new therapies such as citrulline and cinaciguat that will enhance NO synthase and soluble guanylate cyclase function. Continued laboratory and clinical investigation will be needed to optimize treatment and improve outcomes.
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increased p22phox nox4 expression is involved in remodeling through hydrogen peroxide signaling in experimental persistent Pulmonary Hypertension of the newborn
Antioxidants & Redox Signaling, 2013Co-Authors: Stephen Wedgwood, Satyanarayana Lakshminrusimha, Paul T Schumacker, Lyubov Czech, Robin H SteinhornAbstract:Aim: To determine if the NADPH oxidase isoform Nox4 contributes to increased H2O2 generation in persistent Pulmonary Hypertension of the newborn (PPHN) Pulmonary arteries (PA), and to identify downstream signaling targets of Nox4 that contribute to vascular remodeling and vasoconstriction. Results: PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs, PA, and PA smooth muscle cells (PASMC) were isolated from control and PPHN lambs. Increased expression of p22phox and Nox4 in PPHN lungs, PA, and PASMC was associated with increased reactive oxygen species in PPHN PA, increased protein thiol oxidation in PPHN PASMC, and a decreased activity of extracellular superoxide dismutase (ecSOD) in the lungs and PASMC. Nox4 small interfering RNA (siRNA) decreased Nox4 expression and thiol oxidation and increased the ecSOD activity in PPHN PASMC. An increased activity of nuclear factor-kappa B (NFκB) and expression of its target gene cyclin D1 were detected in PPHN lungs, PA, and PASMC. Nox4 siRNA and catalase attenuated these increases in PASMC, and catalase decreased cyclin D1 expression in PPHN lungs. Innovation: This study demonstrates for the first time that Nox4 expression is elevated in a lamb model of Neonatal Pulmonary Hypertension. It identifies increased NFκB and cyclin D1 expression and a decreased ecSOD activity as targets of increased Nox4 signaling. Conclusion: PPHN increases p22phox and Nox4 expression and activity resulting in elevated H2O2 levels in PPHN PA. Increased H2O2 induces vasoconstriction via mechanisms involving ecSOD inactivation, and stimulates vascular remodeling via NFκB activation and increased cyclin D1 expression. Approaches that inhibit the Pulmonary arterial Nox4 activity may attenuate vasoconstriction and vascular remodeling in PPHN. Antioxid. Redox Signal. 18, 1765–1776.
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hydrogen peroxide regulates extracellular superoxide dismutase activity and expression in Neonatal Pulmonary Hypertension
Antioxidants & Redox Signaling, 2011Co-Authors: Stephen Wedgwood, Tohru Fukai, Satyanarayana Lakshminrusimha, James A Russell, Paul T Schumacker, Robin H SteinhornAbstract:Abstract We previously demonstrated that superoxide and H2O2 promote Pulmonary arterial vasoconstriction in a lamb model of persistent Pulmonary Hypertension of the newborn (PPHN). Because extracellular superoxide dismutase (ecSOD) augments vasodilation, we hypothesized that H2O2-mediated ecSOD inactivation contributes to Pulmonary arterial vasoconstriction in PPHN lambs. ecSOD activity was decreased in Pulmonary arterial smooth muscle cells (PASMCs) isolated from PPHN lambs relative to controls. Exposure to 95% O2 to mimic hyperoxic ventilation reduced ecSOD activity in control PASMCs. In both cases, these events were associated with increased protein thiol oxidation, as detected by the redox sensor roGFP. Accordingly, exogenous H2O2 decreased ecSOD activity in control PASMCs, and PEG-catalase restored ecSOD activity in PPHN PASMCs. In intact animal studies, ecSOD activity was decreased in fetal PPHN lambs, and in PPHN lambs ventilated with 100% O2 relative to controls. In ventilated PPHN lambs, administ...
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phosphodiesterases emerging therapeutic targets for Neonatal Pulmonary Hypertension
Handbook of experimental pharmacology, 2011Co-Authors: Kathryn N Farrow, Robin H SteinhornAbstract:Pulmonary Hypertension in the neonate is associated with multiple underlying problems such as respiratory distress syndrome, meconium aspiration syndrome, congenital diaphragmatic hernia, bronchoPulmonary dysplasia, sepsis, or congenital heart disease. Because of the heterogeneous group of disorders, the therapeutic approach and response often depends on the underlying disease. In many of these conditions, there is evidence that cyclic nucleotide signaling and specifically phosphodiesterases (PDEs) are disrupted. PDE inhibitors represent an emerging class of Pulmonary vasodilators in adults. Studies are now under way to evaluate the utility, efficacy, and safety of such therapies in infants with Pulmonary Hypertension.
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Neonatal Pulmonary Hypertension
Pediatric Critical Care Medicine, 2010Co-Authors: Robin H SteinhornAbstract:When the normal cardioPulmonary transition fails to occur, the result is persistent Pulmonary Hypertension of the newborn (PPHN). Severe PPHN is estimated to occur in 2 per 1000 of live born term infants, and some degree of Pulmonary Hypertension complicates the course of more than 10% of all neonates with respiratory failure. This review article discusses the vascular abnormalities that are associated with Neonatal Pulmonary Hypertension, including recognition of its role in severe bronchoPulmonary dysplasia in preterm infants. A systematic review of the evidence for common therapies including inhaled nitric oxide, high frequency ventilation, surfactant, and extracorporeal life support is included. Finally, this field is rapidly evolving, and the rationale for promising new treatment approaches is reviewed, including inhibition of phosphodiesterases and scavengers of reactive oxygen species.
Emilio A Herrera - One of the best experts on this subject based on the ideXlab platform.
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Antenatal melatonin modulates an enhanced antioxidant/pro-oxidant ratio in Pulmonary hypertensive newborn sheep
Elsevier, 2019Co-Authors: Alejandro Gonzalez-candia, German Ebensperger, Roberto V Reyes, Anibal J Llanos, Marcelino Veliz, Catalina Carrasco-pozo, Rodrigo L. Castillo, Cesar J. Cárdenas, Emilio A HerreraAbstract:Chronic hypobaric hypoxia during fetal and Neonatal life induces Neonatal Pulmonary Hypertension. Hypoxia and oxidative stress are driving this condition, which implies an increase generation of reactive oxygen species (ROS) and/or decreased antioxidant capacity. Melatonin has antioxidant properties that decrease oxidative stress and improves Pulmonary vascular function when administered postnatally. However, the effects of an antenatal treatment with melatonin in the Neonatal Pulmonary function and oxidative status are unknown. Therefore, we hypothesized that an antenatal therapy with melatonin improves the Pulmonary arterial pressure and antioxidant status in high altitude Pulmonary hypertensive neonates. Twelve ewes were bred at high altitude (3600 m); 6 of them were used as a control group (vehicle 1.4% ethanol) and 6 as a melatonin treated group (10 mg d-1 melatonin in vehicle). Treatments were given once daily during the last third of gestation (100–150 days). Lambs were born and raised with their mothers until 12 days old, and Neonatal Pulmonary arterial pressure and resistance, plasma antioxidant capacity and the lung oxidative status were determined. Furthermore, we measured the Pulmonary expression and activity for the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, and the oxidative stress markers 8-isoprostanes, 4HNE and nitrotyrosine. Finally, we assessed Pulmonary pro-oxidant sources by the expression and function of NADPH oxidase, mitochondria and xanthine oxidase. Melatonin decreased the birth weight. However, melatonin enhanced the plasma antioxidant capacity and decreased the Pulmonary antioxidant activity, associated with a diminished oxidative stress during postnatal life. Interestingly, melatonin also decreased ROS generation at the main pro-oxidant sources. Our findings suggest that antenatal administration of melatonin programs an enhanced antioxidant/pro-oxidant status, modulating ROS sources in the postnatal lung. Keywords: Oxidative stress, Antioxidant system, Neonatal Pulmonary circulation, Chronic hypoxia, Pulmonary pro-oxidant capacity, DOHa
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role of the rhoa rock pathway in high altitude associated Neonatal Pulmonary Hypertension in lambs
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2016Co-Authors: Nandy Lopez, German Ebensperger, Emilio A Herrera, Roberto V Reyes, Gloria M Calaf, Gertrudis Cabello, Fernando A Moraga, Felipe A Benaldo, Marcela Diaz, Julian T ParerAbstract:Exposure to high-altitude chronic hypoxia during pregnancy may cause Pulmonary Hypertension in neonates, as a result of vasoconstriction and vascular remodeling. We hypothesized that susceptibility to Pulmonary Hypertension, due to an augmented expression and activity of the RhoA/Rho-kinase (ROCK) pathway in these neonates, can be reduced by daily administration of fasudil, a ROCK inhibitor. We studied 10 highland newborn lambs with conception, gestation, and birth at 3,600 m in Putre, Chile. Five highland controls (HLC) were compared with 5 highland lambs treated with fasudil (HL-FAS; 3 mg·kg(-1)·day(-1) iv for 10 days). Ten lowland controls were studied in Lluta (50 m; LLC). During the 10 days of fasudil daily administration, the drug decreased Pulmonary arterial pressure (PAP) and resistance (PVR), basally and during a superimposed episode of acute hypoxia. HL-FAS small Pulmonary arteries showed diminished muscular area and a reduced contractile response to the thromboxane analog U46619 compared with HLC. Hypoxia, but not fasudil, changed the protein expression pattern of the RhoA/ROCKII pathway. Moreover, HL-FAS lungs expressed less pMYPT1(T850) and pMYPT1T(696) than HLC, with a potential increase of the myosin light chain phosphatase activity. Finally, hypoxia induced RhoA, ROCKII, and PKG mRNA expression in PASMCs of HLC, but fasudil reduced them (HL-FAS) similarly to LLC. We conclude that fasudil decreases the function of the RhoA/ROCK pathway, reducing the PAP and PVR in chronically hypoxic highland Neonatal lambs. The inhibition of ROCKs by fasudil may offer a possible therapeutic tool for the Pulmonary Hypertension of the neonates.
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long term exposure to high altitude chronic hypoxia during gestation induces Neonatal Pulmonary Hypertension at sea level
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2010Co-Authors: Emilio A Herrera, German Ebensperger, Roberto V Reyes, Gertrudis Cabello, Julian T Parer, Raquel A Riquelme, Cesar E Ulloa, Bernardo J Krause, Dino A Giussani, Anibal J LlanosAbstract:We determined whether postnatal Pulmonary Hypertension induced by 70% of pregnancy at high altitude (HA) persists once the offspring return to sea level and investigated Pulmonary vascular mechanis...
Daniel J. Penny - One of the best experts on this subject based on the ideXlab platform.
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urotensin ii contributes to Pulmonary vasoconstriction in a perinatal model of persistent Pulmonary Hypertension of the newborn secondary to meconium aspiration syndrome
Pediatric Research, 2010Co-Authors: Catherine M Simpson, Daniel J. Penny, Joseph J Smolich, Lara S ShekerdemianAbstract:Meconium aspiration syndrome (MAS) disrupts perinatal decreases in Pulmonary vascular resistance (PVR) and is the commonest cause of Neonatal Pulmonary Hypertension. The contribution of the potent vasoactive agent urotensin-II (U-II), in the pathophysiology of this condition, is unknown. In a new perinatal model of MAS, we combined measurement of circulating U-II levels with U-II receptor blockade studies. Nineteen anesthetized lambs were instrumented then randomly allocated to the following groups: 1) control (n = 5), 2) control plus specific U-II receptor blockade with palosuran (n = 5), 3) tracheal instillation of meconium (n = 5), 4) meconium instillation plus palosuran (n = 4). Hemodynamics, PVR, and plasma U-II were measured for 6 h after delivery. After birth in controls, U-II increased (p < 0.05), and PVR fell (p = 0.01) and this fall was prevented by U-II receptor blockade. By contrast, meconium lambs displayed a greater rise in U-II levels (p < 0.05 versus control) with an increase in PVR (p < 0.005) that was attenuated by U-II receptor blockade (p < 0.001). These findings suggest that U-II normally acts as a Pulmonary vasodilator after birth, but in the presence of MAS, it assumes a vasoconstrictor role. U-II receptor blockade also improves Pulmonary hemodynamics in this model.
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intravenous sildenafil lowers Pulmonary vascular resistance in a model of Neonatal Pulmonary Hypertension
American Journal of Respiratory and Critical Care Medicine, 2002Co-Authors: Lara Shekerdemian, Hanne Berg Ravn, Daniel J. PennyAbstract:Persistent Pulmonary Hypertension secondary to meconium aspiration syndrome is an important cause of morbidity and mortality in the Neonatal population. We investigated the use of the phosphodiesterase-5 inhibitor sildenafil, in its intravenous form, as a Pulmonary vasodilator in a model of meconium aspiration syndrome. Pulmonary Hypertension was induced in 18 piglets, by endotracheal instillation of human meconium, 6 piglets subsequently received an infusion of intravenous sildenafil for 2 hours, 6 received inhaled nitric oxide for 2 hours, and 6 control animals received no additional intervention. Meconium aspiration increased Pulmonary vascular resistance by 70%, and increased oxygenation index by over 100%. Pulmonary vascular resistance remained elevated for the remainder of the study period in control animals. Inhaled nitric oxide reduced the Pulmonary vascular resistance by 40% after 2 hours of treatment; intravenous sildenafil completely reversed the increase in Pulmonary vascular resistance within 1 hour of commencing the infusion. Neither agent had an effect on systemic hemodynamics. Sildenafil also increased cardiac output by 30%, but while doing so did not adversely influence oxygenation. Intravenous sildenafil is a selective and highly effective Pulmonary vasodilator, which is at least as effective as inhaled nitric oxide, in this model of Neonatal persistent Pulmonary Hypertension.
Sheila G Haworth - One of the best experts on this subject based on the ideXlab platform.
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rac1 and rhoa as regulators of endothelial phenotype and barrier function in hypoxia induced Neonatal Pulmonary Hypertension
American Journal of Physiology-lung Cellular and Molecular Physiology, 2006Co-Authors: Beata Wojciakstothard, Susan M Hall, Lillian Yen Fen Tsang, Ewa Paleolog, Sheila G HaworthAbstract:Hypoxia is a common cause of persistant Pulmonary Hypertension in the newborn (PPHN), a condition associated with endothelial dysfunction and abnormal Pulmonary vascular remodeling. The GTPase RhoA...
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Neonatal Pulmonary Hypertension prevents reorganisation of the Pulmonary arterial smooth muscle cytoskeleton after birth
Journal of Anatomy, 2000Co-Authors: Susan M Hall, Mattias Gorenflo, Jayne A Reader, Durward Lawson, Sheila G HaworthAbstract:The Pulmonary arterial smooth muscle cell (SMC) cytoskeleton was studied in tissue from 36 piglets aged from within 5 min of birth to 21 d of age, and in 8 adults. An additional 16 piglets were made Pulmonary hypertensive by exposure to hypobaric hypoxia (50.8 kPa) for 3 d. In conduit intraPulmonary elastic arteries α, β and γ actin, the 204, 200 and 196 kDa myosin heavy chain (MHC) isoforms and vinculin were localised by immunohistochemistry. The total actin content, the proportion of monomeric to filamentous α and γ actin and changes in the proportions of the MHC isoforms were determined biochemically. Dividing SMCs were localised and quantified using Ki-67. We found a transient reduction in immunohistochemical expression of γ actin, 204 kDa MHC isoform and vinculin at 3 and 6 d in the inner media, associated with a transient increase in Ki-67 labelling. The actin content also decreased at 3 and 6 d (P < 0.05), but there was a postnatal, permanent increase in monomeric actin, first the α then the γ isoform. The relative proportions of the MHC isoforms did not change between birth and adulthood in elastic Pulmonary arteries but in muscular arteries the 200 kDa isoform increased between 14 d and adulthood. Pulmonary Hypertension prevented both the immunohistochemical changes and the postnatal burst of SMC replication and prevented the transient postnatal reduction in actin content. These findings suggest that rapid remodelling of the actin cytoskeleton is an essential prerequisite of a normal postnatal fall in Pulmonary vascular resistance.
