Abstract 19288: Pulmonary Hypertension and Sex Hormone Depletion Affect Lung and Right Ventricular Estrogen Receptor Expression

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Andrea Frump ◽  
Amanda Fisher ◽  
Anthony Cucci ◽  
Marjorie Albrecht ◽  
Kara Goss ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Receptor Expression ◽  
Female Rats ◽  
Sprague Dawley ◽  
Apoptotic Signaling ◽  
Ovx Rats ◽  
Rv Function ◽  
Er Expression

Introduction: Women with pulmonary arterial hypertension exhibit more preserved right ventricular (RV) function than men. The underlying mechanisms are unknown. We measured 17beta-estradiol (E2) levels and lung and RV expression of the two main estrogen receptors (ERalpha and -beta) in male and in intact or ovariectomized (OVX) female rats with Su5416/hypoxia (SuHx)-induced pulmonary hypertension (PH). Hypothesis: E2 is required for adaptation to increased RV afterload in females, and ER expression is inversely correlated with PH severity. Methods: Male and age-matched female Sprague-Dawley rats received Su5416 (20mg/kg), followed by 3 weeks of hypoxia (Patm=362 mmHg) and 4 weeks of room air. Selected females underwent OVX with or without concomitant E2 repletion (75 mcg/kg/d). RV hypertrophy (RV/[LV+S]), RV systolic pressure (RVSP), and PA muscularization were measured; complemented by echocardiographic assessment of RV function and measurement of exercise capacity (VO2max). In addition, we assessed RV pro-apoptotic signaling (bcl-2/bax; caspase-3 activity), serum E2 levels, and lung and RV ER expression by Western blot. N was 7-8/group. P<0.05 was considered significant. Results: While no sex differences were noted in RV/(LV+S), RVSP or PA remodeling, female SuHx rats exhibited more preserved cardiac indices (CI; p<0.05). OVX worsened SuHx-induced alterations in RV hypertrophy, RVSP and CI (p<0.05). In turn, E2 replacement in SuHx-OVX rats prevented SuHx-induced alterations in PH endpoints and RV function; this was accompanied by attenuated RV pro-apoptotic signaling. RV ERbeta decreased in OVX SuHx females, but was restored with E2 repletion (p<0.05). RV ERbeta correlated negatively with RVSP and RV/(LV+S), and positively with RV bcl-2/bax (p<0.05). Similarly, serum E2 levels correlated negatively with RVSP and RV/(LV+S) (p<0.05). While healthy females exhibited higher lung ERbeta than healthy males (p<0.05), no such differences were observed in SuHx-PH. Neither lung nor RV ERalpha was affected by PH or hormone depletion. Conclusions: E2 is required for female adaption to SuHx-PH, through a mechanism that may involve ERbeta-mediated RV cell viability signaling, thus allowing for better adaptation to increases in RV afterload.

scholarly journals Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: effects of endogenous and exogenous sex hormones

2015 ◽  
Vol 308 (9) ◽  
pp. L873-L890 ◽  
Author(s):  
Andrea L. Frump ◽  
Kara N. Goss ◽  
Alexandra Vayl ◽  
Marjorie Albrecht ◽  
Amanda Fisher ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Proinflammatory Cytokine ◽  
Systolic Pressure ◽  
Sprague Dawley ◽  
Mediated Effects ◽  
Ovx Rats ◽  
Sprague Dawley Rats ◽  
Estrogen Effects ◽  
Rv Function

Estrogens are disease modifiers in PAH. Even though female patients exhibit better right ventricular (RV) function than men, estrogen effects on RV function (a major determinant of survival in PAH) are incompletely characterized. We sought to determine whether sex differences exist in RV function in the SuHx model of PAH, whether hormone depletion in females worsens RV function, and whether E2 repletion improves RV adaptation. Furthermore, we studied the contribution of ERs in mediating E2’s RV effects. SuHx-induced pulmonary hypertension (SuHx-PH) was induced in male and female Sprague-Dawley rats as well as OVX females with or without concomitant E2 repletion (75 μg·kg−1·day−1). Female SuHx rats exhibited superior CI than SuHx males. OVX worsened SuHx-induced decreases in CI and SuHx-induced increases in RVH and inflammation (MCP-1 and IL-6). E2 repletion in OVX rats attenuated SuHx-induced increases in RV systolic pressure (RVSP), RVH, and pulmonary artery remodeling and improved CI and exercise capacity (V̇o2max). Furthermore, E2 repletion ameliorated SuHx-induced alterations in RV glutathione activation, proapoptotic signaling, cytoplasmic glycolysis, and proinflammatory cytokine expression. Expression of ERα in RV was decreased in SuHx-OVX but was restored upon E2 repletion. RV ERα expression was inversely correlated with RVSP and RVH and positively correlated with CO and apelin RNA levels. RV-protective E2 effects observed in females were recapitulated in male SuHx rats treated with E2 or with pharmacological ERα or ERβ agonists. Our data suggest significant RV-protective ER-mediated effects of E2 in a model of severe PH.

Abstract 230: Gender Differences in the Development of Experimental Pulmonary Hypertension and Associated Right Ventricular Remodeling: The Role of Estrogen Rescue

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Soban Umar ◽  
Rangarajan Nadadur ◽  
Mansoureh Eghbali
Keyword(s):  
Gender Differences ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Ventricular Remodeling ◽  
Therapeutic Potential ◽  
Systolic Pressure ◽  
Female Rats ◽  
Male And Female ◽  
Male And Female Rats ◽  
Ovx Rats

17-beta estradiol or Estrogen (E2) pre-treatment has been shown to attenuate the development of pulmonary hypertension (PH). Here, we aim to investigate the gender differences and the effect of ovariectomy on the development of experimental PH and adverse right ventricular (RV) remodeling. We also evaluate the therapeutic potential of E2 in rescuing PH and adverse RV remodelling in male and female rats. Male and female (intact and ovariectomized (OVX)) rats were treated with a single injection of monocrotaline (MCT, 60mg/kg, s.c.) to induce PH. Twenty one days after MCT, rats developed severe PH. At this point, one set of rats from each group was left untreated to develop PH-induced right ventricular failure (RVF), whereas the other set received E2 (42.5 ug/kg/day, 10-day slow release s.c. pellets). E2-treated rats were observed for an additional 12 days after cessation of therapy to check whether the effects of therapy were long-lived. Saline treated rats served as control (CTRL). Serial echocardiography was performed to monitor cardiopulmonary hemodynamics. Direct RV catheterization was terminally performed to record RV peak systolic pressure (RVPSP). The expression of novel extracellular matrix (ECM) enzymes A Disintegrin And Metalloproteinase (ADAM15 and 17) and Osteopontin (OPN) were assessed by RT-PCR. Intact females developed less severe PH than males and OVX females at day 30 (RVPSP: Females=62±3, Males=74±3, OVX=77±3 mm Hg, p<0.05 vs. respective CTRL). E2 therapy resulted in rescue of PH in all groups (RVPSP: Females=36±4, Males=38±2, OVX=44±2 mm Hg, p<0.05 vs. respective PH-RVF). Intact females also developed less severe RV remodeling compared to males and OVX females. Expression of OPN increased ∼7-9-fold in PH-RVF males and OVX but only ∼2-fold in intact females, (p<0.05 vs. CTRL for all). E2 reversed OPN upregulation in all groups (p<0.05 vs. PH-RVF). Novel ECM-degrading Disintegrin-Metalloproteinases ADAM15 and ADAM17 transcripts were also elevated ∼2-fold in all PH-RVF animals (p<0.05 vs. CTRL). E2-therapy reversed RV remodeling in all groups (p<0.05 vs. PH-RVF). In conclusion, intact females are more protected against the development of PH compared to males and OVX females. E2 rescues PH and adverse RV remodeling in all groups.

scholarly journals 17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension

2016 ◽  
Vol 311 (2) ◽  
pp. L375-L388 ◽  
Author(s):  
Tim Lahm ◽  
Andrea L. Frump ◽  
Marjorie E. Albrecht ◽  
Amanda J. Fisher ◽  
Todd G. Cook ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Aerobic Capacity ◽  
Acute Exercise ◽  
Female Rats ◽  
Autophagic Flux ◽  
Protective Effects ◽  
Exercise Challenge ◽  
17Β Estradiol ◽  
Rv Function

17β-Estradiol (E2) exerts protective effects on right ventricular (RV) function in pulmonary arterial hypertension (PAH). Since acute exercise-induced increases in afterload may lead to RV dysfunction in PAH, we sought to determine whether E2 allows for superior RV adaptation after an acute exercise challenge. We studied echocardiographic, hemodynamic, structural, and biochemical markers of RV function in male and female rats with sugen/hypoxia (SuHx)-induced pulmonary hypertension, as well as in ovariectomized (OVX) SuHx females, with or without concomitant E2 repletion (75 μg·kg−1·day−1) immediately after 45 min of treadmill running at 75% of individually determined maximal aerobic capacity (75% aerobic capacity reserve). Compared with males, intact female rats exhibited higher stroke volume and cardiac indexes, a strong trend for better RV compliance, and less pronounced increases in indexed total pulmonary resistance. OVX abrogated favorable RV adaptations, whereas E2 repletion after OVX markedly improved RV function. E2's effects on pulmonary vascular remodeling were complex and less robust than its RV effects. Postexercise hemodynamics in females with endogenous or exogenous E2 were similar to hemodynamics in nonexercised controls, whereas OVX rats exhibited more severely altered postexercise hemodynamics. E2 mediated inhibitory effects on RV fibrosis and attenuated increases in RV collagen I/III ratio. Proapoptotic signaling, endothelial nitric oxide synthase phosphorylation, and autophagic flux markers were affected by E2 depletion and/or repletion. Markers of impaired autophagic flux correlated with endpoints of RV structure and function. Endogenous and exogenous E2 exerts protective effects on RV function measured immediately after an acute exercise challenge. Harnessing E2's mechanisms may lead to novel RV-directed therapies.

Abstract 17280: A New in vivo Imaging Protocol for Non-Invasive Detection of Right Ventricular Dysfunction in a Pulmonary Hypertension Mouse Model

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Thomas Hansen ◽  
Kristen Bubb ◽  
Gemma Figtree
Keyword(s):  
Pulmonary Hypertension ◽  
Mouse Model ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Saline Control ◽  
Novel Therapies ◽  
Imaging Protocol ◽  
Non Invasive ◽  
Rv Function

Introduction: Accurate measurements of right ventricular (RV) function are critical for studying novel therapies impacting the heart and pulmonary circulation. Until now, assessment in mouse models has relied on invasive measures. Improvements in mouse echocardiography may facilitate application of measures recently validated in humans, including tricuspid annular plane systolic excursion (TAPSE) and RV-S’ (systolic excursion velocity), to allow non-invasive assessment of RV function. Aims: To apply and validate TAPSE and RV-S’ using high-resolution echocardiography for the measurement of RV function in a mouse model of pulmonary hypertension (PH). Methods: Echocardiography was performed on mice 3 weeks after induction of PH using inhaled bleomycin or saline control. PAT, TAPSE and RV-S’ were recorded in mice using a 55-mHz transducer (Visualsonics, Vevo3100). Invasive measurements of right ventricular systolic pressure (RVSP) were obtained via catheterisation of the internal jugular vein, prior to culling. Results: RVSP was significantly elevated in bleomycin-treated mice ( 33.41±0.8mmHg n=10) compared to controls ( 25.66±0.9mmHg n=11; p<0.0001). Similarly, RV hypertrophy was observed in bleomycin mice [RV:body weight 1.156±0.03g/kg n=11] compared with control ( 0.968±0.02g/kg n=12; p=0.0002). TAPSE was sensitive to these differences, being significantly reduced in bleomycin mice ( 0.5739±0.020mm n=8) compared with control ( 0.7387±0.033mm n=10; p=0.0012), and correlated significantly with invasive RVSP (r 2 =0.7218; p<0.0001). RV-S’ was also reduced in bleomycin mice (18.14±0.98mm/s n=7) compared with control (25.38±1.24mm/s n=8; p=0.0006) and correlated strongly with RVSP (r 2 =0.6378; p=0.0011). The correlation of both TAPSE and RV-S’ with RVSP compared favourably to the previously used surrogate measure of RVSP in mice, PAT (r 2 =0.5278; p=0.0002). Conclusions: TAPSE and RV-S’ can be applied in mouse echocardiography, and are sensitive, non-invasive measures of PH and RV dysfunction, comparing well with gold-standard invasive right ventricular systolic pressures. This may benefit the power of future preclinical studies of novel therapies in pulmonary hypertension and RV dysfunction.

scholarly journals The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension

2021 ◽  
Vol 22 (18) ◽  
pp. 9916
Author(s):  
Vijaya Karoor ◽  
Derek Strassheim ◽  
Timothy Sullivan ◽  
Alexander Verin ◽  
Nagavedi S. Umapathy ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Protective Effect ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Histone H3 ◽  
Systolic Pressure ◽  
Right Heart Failure ◽  
Sprague Dawley ◽  
Pulmonary Vascular Remodeling ◽  
Ventricular Systolic Pressure

Pulmonary hypertension (PH) is a progressive cardiovascular disorder in which local vascular inflammation leads to increased pulmonary vascular remodeling and ultimately to right heart failure. The HDAC inhibitor butyrate, a product of microbial fermentation, is protective in inflammatory intestinal diseases, but little is known regarding its effect on extraintestinal diseases, such as PH. In this study, we tested the hypothesis that butyrate is protective in a Sprague–Dawley (SD) rat model of hypoxic PH. Treatment with butyrate (220 mg/kg intake) prevented hypoxia-induced right ventricular hypertrophy (RVH), hypoxia-induced increases in right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, and permeability. A reversal effect of butyrate (2200 mg/kg intake) was observed on elevated RVH. Butyrate treatment also increased the acetylation of histone H3, 25–34 kDa, and 34–50 kDa proteins in the total lung lysates of butyrate-treated animals. In addition, butyrate decreased hypoxia-induced accumulation of alveolar (mostly CD68+) and interstitial (CD68+ and CD163+) lung macrophages. Analysis of cytokine profiles in lung tissue lysates showed a hypoxia-induced upregulation of TIMP-1, CINC-1, and Fractalkine and downregulation of soluble ICAM (sICAM). The expression of Fractalkine and VEGFα, but not CINC-1, TIMP-1, and sICAM was downregulated by butyrate. In rat microvascular endothelial cells (RMVEC), butyrate (1 mM, 2 and 24 h) exhibited a protective effect against TNFα- and LPS-induced barrier disruption. Butyrate (1 mM, 24 h) also upregulated tight junctional proteins (occludin, cingulin, claudin-1) and increased the acetylation of histone H3 but not α-tubulin. These findings provide evidence of the protective effect of butyrate on hypoxic PH and suggest its potential use as a complementary treatment for PH and other cardiovascular diseases.

scholarly journals Combination therapy improves vascular volume in female rats with pulmonary hypertension

2019 ◽  
Vol 317 (4) ◽  
pp. L445-L455 ◽  
Author(s):  
Daniel J. Lachant ◽  
David F. Meoli ◽  
Deborah Haight ◽  
Serban Staicu ◽  
Shanti Akers ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Combination Therapy ◽  
Severe Disease ◽  
Systolic Pressure ◽  
Middle Lobe ◽  
Female Rats ◽  
Male Rats ◽  
Receive Combination Therapy ◽  
Sprague Dawley ◽  
Vascular Volume

Pulmonary arterial hypertension (PAH) is a female predominant disease in which progressive vascular remodeling and vasoconstriction result in right ventricular (RV) failure and death. Most PAH patients utilize multiple therapies. In contrast, the majority of preclinical therapeutic studies are performed in male rats with a single novel drug often markedly reversing disease in the model. We sought to differentiate single drug therapy from combination therapy in female rats with severe disease. One week after left pneumonectomy, we induced PH in young female Sprague-Dawley rats with an injection of monocrotaline (45 mg/kg). Female rats were then randomized to receive combination therapy (ambrisentan plus tadalafil), ambrisentan monotherapy, tadalafil monotherapy, or vehicle. We measured RV size and function on two serial echocardiograms during the development of disease. We measured RV systolic pressure (RVSP) invasively at day 28 after monocrotaline before analyzing the vascular volume with microcomputed tomography (microCT) of the right middle lobe. RVSP was significantly lower in female rats treated with combination therapy, and combination therapy resulted in increased small vessel volume density measured by microCT compared with untreated rats. Combination-treated rats had the smallest RV end-diastolic diameter on echocardiogram as compared with the other groups. In summary, we report a female model of pulmonary hypertension that can distinguish between one and two drug therapies; this model may facilitate better preclinical drug testing for novel compounds.

Abstract P600: Activation Of GPER Ameliorates Pulmonary Hypertension In Female Rats

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Gisele Zapata-Sudo ◽  
Allan K Alencar ◽  
Daniele Gabriel-Costa ◽  
Ananssa M Silva ◽  
Guilherme C Montes ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Exercise Capacity ◽  
Systolic Pressure ◽  
New Drugs ◽  
Female Rats ◽  
Exercise Intolerance ◽  
Time To Exhaustion ◽  
Bilateral Oophorectomy ◽  
Altered Expression ◽  
Ovx Rats

Introduction: Pulmonary hypertension (PH) is primarily a disease of women (female-to-male ratio 4:1) and is associated with cardiac dysfunction. Aim: The activation of GPER by its agonist G1 was evaluated in monocrotaline (MCT)-induced PH rats. Methods: Depletion of estrogen was induced by bilateral oophorectomy (OVX; n = 18) in female Wistar rats (12 wks old). Experimental groups were: SHAM or OVX that received i.p. injection of MCT (60 mg/kg) for PH induction followed by administration of vehicle or G1 (400 μg/kg/day s.c.) for 14 days (n=7 per group). Hemodynamic parameters were determined by echocardiography. The effects of G1 in the maintenance of exercise capacity was investigated using a treadmill test. Results: MCT injection and estrogen loss led to a significant decrease in pulmonary acceleration time (PAT) and an increase in RV free wall thickness and MCT-related changes were attenuated by treatment with G1 ( P < 0.05; Table 1). Right ventricular systolic pressure (RVSP) was higher in MCT-injected rats and the magnitude of this increase in OVX group was significantly higher than that in SHAM group. G1 normalized RVSP in both SHAM and OVX rats (Table 1). G1 treatment reversed altered expression of SERCA2a and phospholamban proteins in the RV (Table 1). Interaction between estrogen loss and MCT also reduced treadmill time to exhaustion in PH rats ( P < 0.05), and chronic administration of G1 restored the exercise capacity ( P < 0.05). Conclusion: G1 reversed PH-related cardiopulmonary dysfunction and exercise intolerance in female rats, a finding that may have important implications for the ongoing clinical evaluation of new drugs for the treatment of the disease in aging females.

Right ventricular pressure-volume loop shape and systolic pressure change in pulmonary hypertension

2021 ◽  
Author(s):  
Manuel Jonas Richter ◽  
Steven Hsu ◽  
Athiththan Yogeswaran ◽  
Faeq Husain-Syed ◽  
István Vadász ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Pulse Pressure ◽  
Augmentation Index ◽  
Systolic Pressure ◽  
Pressure Differential ◽  
Stroke Work ◽  
Loop Shape ◽  
Pulmonary Arterial ◽  
Rv Function

Right ventricular (RV) function determines outcome in pulmonary arterial hypertension (PAH). RV pressure-volume loops - the gold standard for measuring RV function - are difficult to analyze. Our aim was to investigate whether simple assessments of RV pressure-volume loop morphology and RV systolic pressure differential reflect PAH severity and RV function. We analyzed multi-beat RV pressure-volume loops (obtained by conductance catheterization with preload reduction) in 77 patients with PAH and 15 patients without pulmonary hypertension in two centers. Patients were categorized according to their pressure-volume loop shape (triangular, quadratic, trapezoid, or notched). RV systolic pressure differential was defined as end-systolic minus beginning-systolic pressure (ESP−BSP); augmentation index as ESP−BSP/pulse pressure; pulmonary arterial capacitance (PAC) as stroke volume/pulse pressure; and RV-arterial coupling as end-systolic/arterial elastance (Ees/Ea). Trapezoid and notched pressure-volume loops were associated with the highest afterload (Ea), augmentation index, pulmonary vascular resistance (PVR), mean pulmonary arterial pressure, stroke work, and B-type natriuretic peptide, and the lowest Ees/Ea and PAC. Multivariate linear regression identified Ea, PVR, and stroke work as the main determinants of ESP−BSP. ESP−BSP also significantly correlated with multi-beat Ees/Ea (Spearman's rho: −0.518, P < 0.001). A separate retrospective analysis of 113 patients with PAH showed that ESP−BSP obtained by routine right heart catheterization significantly correlated with a non-invasive surrogate of RV-arterial coupling (tricuspid annular plane systolic excursion/pulmonary arterial systolic pressure ratio; rho: −0.376, P < 0.001). In conclusion, pressure-volume loop shape and RV systolic pressure differential predominately depend on afterload and PAH severity and reflect RV-arterial coupling in PAH.

scholarly journals Enhanced NO-dependent pulmonary vasodilation limits increased vasoconstrictor sensitivity in neonatal chronic hypoxia

2017 ◽  
Vol 313 (4) ◽  
pp. H828-H838 ◽  
Author(s):  
Joshua R. Sheak ◽  
Laura Weise-Cross ◽  
Ray J. deKay ◽  
Benjimen R. Walker ◽  
Nikki L. Jernigan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Chronic Hypoxia ◽  
Systolic Pressure ◽  
Sprague Dawley ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Vasodilation ◽  
Basal Tone

Augmented vasoconstrictor reactivity is thought to play an important role in the development of chronic hypoxia (CH)-induced neonatal pulmonary hypertension. However, whether this response to CH results from pulmonary endothelial dysfunction and reduced nitric oxide (NO)-mediated vasodilation is not well understood. We hypothesized that neonatal CH enhances basal tone and pulmonary vasoconstrictor sensitivity by limiting NO-dependent pulmonary vasodilation. To test this hypothesis, we assessed the effects of the NO synthase (NOS) inhibitor Nω-nitro-l-arginine (l-NNA) on baseline pulmonary vascular resistance (PVR) and vasoconstrictor sensitivity to the thromboxane mimetic U-46619 in saline -perfused lungs (in situ) from 2-wk-old control and CH (12-day exposure, 0.5 atm) Sprague-Dawley rats. Basal tone was defined as that reversed by exogenous NO (spermine NONOate). CH neonates displayed elevated right ventricular systolic pressure (in vivo) and right ventricular hypertrophy, indicative of pulmonary hypertension. Perfused lungs from CH rats demonstrated greater baseline PVR, basal tone, and U-46619-mediated vasoconstriction compared with control rats in the absence of l-NNA. l-NNA markedly increased baseline PVR and reactivity to U-46619 in lungs from CH neonates, further augmenting vasoconstrictor sensitivity compared with control lungs. Exposure to CH also enhanced NO-dependent vasodilation to arginine vasopressin, pulmonary expression of NOS III [endothelial NOS (eNOS)], and eNOS phosphorylation at activation residue Ser1177. However, CH did not alter lung nitrotyrosine levels, a posttranslational modification reflecting [Formula: see text] scavenging of NO. We conclude that, in contrast to our hypothesis, enhanced basal tone and agonist-induced vasoconstriction after neonatal CH is limited by increased NO-dependent pulmonary vasodilation resulting from greater eNOS expression and phosphorylation at activation residue Ser1177. NEW & NOTEWORTHY This research is the first to demonstrate enhanced nitric oxide-dependent vasodilation that limits increased vasoconstrictor reactivity in neonatal pulmonary hypertension. These results suggest that augmented vasoconstriction in this setting reflects changes in smooth muscle reactivity rather than a reduction in nitric oxide-dependent pulmonary vasodilation.

Increased expression of PDGF A- and B-chain genes in rat lungs with hypoxic pulmonary hypertension

1993 ◽  
Vol 264 (2) ◽  
pp. L100-L106 ◽  
Author(s):  
D. Katayose ◽  
M. Ohe ◽  
K. Yamauchi ◽  
M. Ogata ◽  
K. Shirato ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Mrna Level ◽  
Systolic Pressure ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Pulmonary Vascular Remodeling ◽  
Ventricular Systolic Pressure ◽  
A Chain

To study the molecular basis of vascular remodeling in pulmonary hypertension, we developed an experimental system in which male Sprague-Dawley rats were exposed to hypoxia for up to 3 wk. Both the right ventricular systolic pressure and gravimetric index for right ventricular hypertrophy were higher in rats exposed to hypoxia for 3 wk than those of age-matched control rats (P < 0.01), indicating that pulmonary hypertension was established under conditions used. To examine the possible involvement of platelet-derived growth factor (PDGF) in the pulmonary vascular remodeling caused by hypoxia, we cloned rat PDGF A- and B-chain cDNA and prepared specific cRNA probes. Northern blot analysis revealed that PDGF B-chain mRNA levels in the lungs were increased, reached a maximum of day 1, and were sustained at day 3, whereas PDGF A-chain mRNA levels reached a maximum on day 3. Thus the increase in the PDGF B-chain mRNA level precedes that in the PDGF A-chain mRNA level. These results suggest that the PDGF A- and B-chain products may be coordinately and sequentially involved in hypoxic pulmonary vascular remodeling.

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