Deletion of the eNOS gene has a greater impact on the pulmonary circulation of male than female mice

2005 ◽  
Vol 289 (2) ◽  
pp. L299-L366 ◽  
Author(s):  
Alyson A. Miller ◽  
Alison A. Hislop ◽  
Patrick J. Vallance ◽  
Sheila G. Haworth
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Adult Male ◽  
Pulmonary Circulation ◽  
Adult Life ◽  
Enos Gene ◽  
Fetal Life ◽  
Male And Female ◽  
Female Mice

Nitric oxide is involved in development and postnatal adaptation of the pulmonary circulation. This study aimed to determine whether genetic deletion of nitric oxide synthase (NOS) would lead to maldevelopment of the pulmonary arteries in fetal life, compromise adaptation to extrauterine life, and be associated with a pulmonary hypertensive phenotype in adult life and if any abnormalities were detected, were they sex dependent. Morphometric analyses were made on lung tissue from male and female fetal, newborn, 14-day-old, and adult endothelial NOS-deficient (eNOS−/−) or inducible NOS-deficient (iNOS−/−) and wild-type mice. Hemodynamic studies were carried out on adult mice with deletion of either eNOS or iNOS genes. We found that in eNOS−/− mice, lung development was normal in fetal, newborn, and adult lungs. Pulmonary arterial muscularity was greater than normal in both male and female eNOS−/− during fetal life and at birth, but the abnormality persisted only in male mice. Right ventricular hypertrophy was present in 14-day-old and adult male eNOS−/− but not in female mice. Adult male eNOS−/− mice had higher mean right ventricular and systemic pressures than female eNOS−/− mice ( P < 0.05). Thus deletion of the eNOS gene was associated with structural evidence of pulmonary hypertension in both sexes during fetal life, but pulmonary hypertension persisted only in the male. In neither sex did iNOS or neuronal NOS appear to compensate for the eNOS deletion. Adult iNOS−/− mice did not have structural or hemodynamic evidence of pulmonary hypertension. Possible compensatory mechanisms are discussed.

Abstract P141: Gender Differences in the Development of Severe Pulmonary Hypertension and Right Ventricular Dysfunction in Apolipoprotein E--Deficient Mice Are Eliminated with Increasing Age

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Rod Partow-Navid ◽  
Soban Umar ◽  
Humann Matori ◽  
Andrea Iorga ◽  
Alan M Fogelman ◽  
...  
Keyword(s):  
Gender Differences ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Apolipoprotein E ◽  
Young Male ◽  
Male Mice ◽  
Male And Female ◽  
Young Females ◽  
Female Mice ◽  
Deficient Mice

Apolipoprotein E (ApoE) is a multifunctional protein and its deficiency leads to the development of atherosclerosis in mice. Patients with pulmonary hypertension (PH) have reduced expression of ApoE in lung tissue. ApoE is known to inhibit endothelial and smooth muscle cell proliferation and has anti-inflammatory and anti-platelet aggregation properties. Young ApoE deficient mice have been shown to develop high fat diet-induced PH in a gender specific manner. Estrous cyclicity peaks at 7–8 months and declines by 9 months of age in mice. Here we investigated the effects of monocrotaline (MCT) on young and middle-aged ApoE deficient mice.Middle-Aged (MA) (11–12 month old) male (n=4) and female (n=4) and young (7–8 month old) male (n=5) and female (n=5) ApoE deficient mice were injected with a single intraperitoneal dose of MCT (60 mg/kg). Mice were closely monitored for ∼4 weeks with serial echocardiography for cardiopulmonary hemodynamic assessment. Direct cardiac catheterisation was performed terminally to record peak systolic right ventricular pressure (RVP). RV, LV, IVS and lung tissue was dissected and weighed. Trichrome staining and histochemical analyses were performed. At ∼4 weeks after MCT, MA male and female and young male mice developed severe PH (RVP: MA male=64±5 mmHg, MA female=71±4 mmHg, young male=60±5 mmHg, p=n.s between all the groups) whereas young females developed significantly less severe PH (RVP: 37±5 mmHg, P<0.05 vs. MA male and female, and young male). MA male and female and young male mice developed severe RV dysfunction (RV ejection fraction (RVEF): MA male=31±2%, MA female=28±4%, young male=36±1%, p=n.s between all the groups) whereas young females showed significantly better RV function (RVEF: 43±2%, P<0.05 vs. MA male and female, and young male). MA male and female mice also developed more severe RV hypertrophy (RV/LV+Septum, MA male=0.49, MA female=0.53, young female=0.39). MA male and female mice also manifested increased peripheral pulmonary artery muscularization and pulmonary fibrosis. Interestingly, the gender differences witnessed between young ApoE deficient male and female mice in the development of severe PH and RV dysfunction are abolished as the mice increase in age.

Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase

2004 ◽  
Vol 287 (4) ◽  
pp. L656-L664 ◽  
Author(s):  
Karen A. Fagan ◽  
Masahiko Oka ◽  
Natalie R. Bauer ◽  
Sarah A. Gebb ◽  
D. Dunbar Ivy ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Pulmonary Circulation ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Rho Kinase ◽  
Hypoxic Pulmonary Hypertension ◽  
Pulmonary Vasoconstriction

RhoA GTPase mediates a variety of cellular responses, including activation of the contractile apparatus, growth, and gene expression. Acute hypoxia activates RhoA and, in turn, its downstream effector, Rho-kinase, and previous studies in rats have suggested a role for Rho/Rho-kinase signaling in both acute and chronically hypoxic pulmonary vasoconstriction. We therefore hypothesized that activation of Rho/Rho-kinase in the pulmonary circulation of mice contributes to acute hypoxic pulmonary vasoconstriction and chronic hypoxia-induced pulmonary hypertension and vascular remodeling. In isolated, salt solution-perfused mouse lungs, acute administration of the Rho-kinase inhibitor Y-27632 (1 × 10−5 M) attenuated hypoxic vasoconstriction as well as that due to angiotensin II and KCl. Chronic treatment with Y-27632 (30 mg·kg−1·day−1) via subcutaneous osmotic pump decreased right ventricular systolic pressure, right ventricular hypertrophy, and neomuscularization of the distal pulmonary vasculature in mice exposed to hypobaric hypoxia for 14 days. Analysis of a small number of proximal pulmonary arteries suggested that Y-27632 treatment reduced the level of phospho-CPI-17, a Rho-kinase target, in hypoxic lungs. We also found that endothelial nitric oxide synthase protein in hypoxic lungs was augmented by Y-27632, suggesting that enhanced nitric oxide production might have played a role in the Y-27632-induced attenuation of chronically hypoxic pulmonary hypertension. In conclusion, Rho/Rho-kinase activation is important in the effects of both acute and chronic hypoxia on the pulmonary circulation of mice, possibly by contributing to both vasoconstriction and vascular remodeling.

Early Life Exposure to Antibiotic Alters Energy Balance during Chronic High-Fat Feeding in Adult Male and Female Mice

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1999-P ◽  
Author(s):  
HYE LIM NOH ◽  
SUJIN SUK ◽  
RANDALL H. FRIEDLINE ◽  
KUNIKAZU INASHIMA ◽  
DUY A. TRAN ◽  
...  
Keyword(s):  
Energy Balance ◽  
Adult Male ◽  
Early Life ◽  
High Fat ◽  
Male And Female ◽  
Female Mice ◽  
Early Life Exposure ◽  
Fat Feeding

Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension

1998 ◽  
Vol 84 (2) ◽  
pp. 435-441 ◽  
Author(s):  
Christophe Adrie ◽  
Fumito Ichinose ◽  
Alexandra Holzmann ◽  
Larry Keefer ◽  
William E. Hurford ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Vascular Resistance ◽  
Pulmonary Circulation ◽  
Half Life ◽  
Hemodynamic Effects ◽  
Pulmonary Vasodilation ◽  
Short Half Life ◽  
Acute Pulmonary Hypertension ◽  
Inhaled No

Adrie, Christophe, Fumito Ichinose, Alexandra Holzmann, Larry Keefer, William E. Hurford, and Warren M. Zapol. Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension. J. Appl. Physiol. 84(2): 435–441, 1998.—Sodium 1-( N, N-diethylamino)diazen-1-ium-1,2-diolate {DEA/NO; Et2N[N(O)NO]Na} is a compound that spontaneously generates nitric oxide (NO). Because of its short half-life (2.1 min), we hypothesized that inhaling DEA/NO aerosol would selectively dilate the pulmonary circulation without decreasing systemic arterial pressure. We compared the pulmonary selectivity of this new NO donor with two other reference drugs: inhaled NO and inhaled sodium nitroprusside (SNP). In seven awake sheep with pulmonary hypertension induced by the infusion of U-46619, we compared the hemodynamic effects of DEA/NO with those of incremental doses of inhaled NO gas. In seven additional awake sheep, we examined the hemodynamic effects of incremental doses of inhaled nitroprusside (i.e., SNP). Inhaled NO gas selectively dilated the pulmonary vasculature. Inhaled DEA/NO produced nonselective vasodilation; both systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were reduced. Inhaled SNP selectively dilated the pulmonary circulation at low concentrations (≤10−2 M), inducing a decrease of PVR of up to 42% without any significant decrease of SVR (−5%), but nonselectively dilated the systemic circulation at larger doses (>10−2 M). In conclusion, despite its short half-life, DEA/NO is not a selective pulmonary vasodilator compared with inhaled NO. Inhaled SNP appears to be selective to the pulmonary circulation at low doses but not at higher levels.

scholarly journals Exogenous Ghrelin Attenuates the Progression of Chronic Hypoxia-Induced Pulmonary Hypertension in Conscious Rats

Endocrinology ◽  
2007 ◽  
Vol 149 (1) ◽  
pp. 237-244 ◽  
Author(s):  
Daryl O. Schwenke ◽  
Takeshi Tokudome ◽  
Mikiyasu Shirai ◽  
Hiroshi Hosoda ◽  
Takeshi Horio ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Endothelial Nitric Oxide Synthase ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Arterial ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Chronic exposure to hypoxia, a common adverse consequence of most pulmonary disorders, can lead to a sustained increase in pulmonary arterial pressure (PAP), right ventricular hypertrophy, and is, therefore, closely associated with heart failure and increased mortality. Ghrelin, originally identified as an endogenous GH secretagogue, has recently been shown to possess potent vasodilator properties, likely involving modulation of the vascular endothelium and its associated vasoactive peptides. In this study we hypothesized that ghrelin would impede the pathogenesis of pulmonary arterial hypertension during chronic hypoxia (CH). PAP was continuously measured using radiotelemetry, in conscious male Sprague Dawley rats, in normoxia and during 2-wk CH (10% O2). During this hypoxic period, rats received a daily sc injection of either saline or ghrelin (150 μg/kg). Subsequently, heart and lung samples were collected for morphological, histological, and molecular analyses. CH significantly elevated PAP in saline-treated rats, increased wall thickness of peripheral pulmonary arteries, and, consequently, induced right ventricular hypertrophy. In these rats, CH also led to the overexpression of endothelial nitric oxide synthase mRNA and protein, as well as endothelin-1 mRNA within the lung. Exogenous ghrelin administration attenuated the CH-induced overexpression of endothelial nitric oxide synthase mRNA and protein, as well as endothelin-1 mRNA. Consequently, ghrelin significantly attenuated the development of pulmonary arterial hypertension, pulmonary vascular remodeling, and right ventricular hypertrophy. These results demonstrate the therapeutic benefits of ghrelin for impeding the pathogenesis of pulmonary hypertension and right ventricular hypertrophy, particularly in subjects prone to CH (e.g. pulmonary disorders).

Vascular Dysfunction in Murine Models of Hemolytic Anemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 846-846
Author(s):  
Nancy J. Wandersee ◽  
Anne C. Frei ◽  
Sandra L. Holzhauer ◽  
J. Paul Scott ◽  
Kirkwood A. Pritchard ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Oxidative Damage ◽  
Right Ventricular ◽  
Hemolytic Anemia ◽  
Vascular Dysfunction ◽  
Murine Models ◽  
Intravascular Hemolysis ◽  
Scavenging Capacity ◽  
Healthy Control

Abstract Pulmonary hypertension affects approximately 30% of young adults with sickle cell disease (SCD) and is a risk factor for early death. There is increasing evidence that intravascular hemolysis contributes to the pathophysiology of pulmonary hypertension in SCD as well as other hemolytic disorders. In this study, we compare measures of vascular dysfunction in Berkeley sickle cell mice (SCD mice) with a murine model of hereditary spherocytosis (sph/sph mice) that exhibit severe hemolytic anemia due to alpha spectrin deficiency, but without HbS-induced RBC sickling. We assessed right ventricular systolic pressure in vivo as a measure of pulmonary arterial function and endothelial-dependent vasodilation of facialis arteries ex vivo as a measure of systemic arterial function. Right ventricular systolic pressures and right ventricle to body weight ratios were increased to similar levels in both SCD and sph/sph mice as compared to control mice (p <0.025), consistent with pulmonary hypertension in both SCD and sph/sph mice. Acetylcholine-induced vasodilation of facialis arteries (a branch of the carotid artery) was severely impaired in both SCD and sph/sph mice compared to control mice (p<0.02). We also found increased plasma levels of soluble VCAM-1, E-selectin, and P-selectin in SCD and sph/sph mice compared to control mice (p<0.005 for all groups), providing further evidence for increased endothelial injury in both murine models. Interestingly, sVCAM-1 and E-selectin were more elevated in SCD mice compared to sph/sph mice (p<0.0001), suggesting hemolysis combined with HbS induces further endothelial injury. We hypothesized that plasma free hemoglobin released by intravascular hemolysis initiates endothelial impairment and injury due to scavenging of nitric oxide (NO) and generation of oxidative damage. Plasma methemoglobin levels were determined by helium electron paramagnetic resonance (EPR) spectroscopy before and after the addition of the NO donor molecule PROLI/NO. The difference between these two signals represents the total NO scavenging capacity of plasma. We found that both the plasma free Hb and NO scavenging capacity in plasma from SCD and sph/sph mice was much greater than that of healthy control mice (p<0.05). In addition, we developed an oxygen electrode assay to assess the oxidizing potential of plasma. The initiation of lipid peroxidation by oxidants present in the plasma results in the consumption of oxygen. We found that plasma from SCD and sph/sph mice has a significantly higher oxidizing potential than plasma from control mice (p<0.05). We obtained similar results (increased plasma free Hb, NO scavenging capacity, and oxidizing potential) comparing plasma from individuals with SCD to plasma from healthy control individuals. Consistent with the higher levels of hemolysis in the sph/sph mice, plasma free Hb, NO scavenging and oxidizing capacity were greater in sph/sph mice compared SCD mice (p<0.05). These results indicate that both pulmonary and systemic vascular function is impaired in these two different murine models of hemolysis, and suggest that nitric oxide-based vasoregulatory mechanisms are particularly affected. These data, combined with previous pathologic reports, suggest that while hemolysis importantly contributes to aberrant vasoregulation and initiating pathways of oxidative damage, sickle hemoglobin may uniquely provoke additional vascular and organ injury.

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