Role of VEGF-B in the lung during development of chronic hypoxic pulmonary hypertension

2003 ◽  
Vol 284 (6) ◽  
pp. L926-L937 ◽  
Author(s):  
Vanessa Louzier ◽  
Bernadette Raffestin ◽  
Aude Leroux ◽  
Didier Branellec ◽  
Jean Michel Caillaud ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Weight Ratio ◽  
Adenovirus Vector ◽  
Vascular Density ◽  
Protective Effects ◽  
Enos Expression ◽  
Lung Weight ◽  
Pulmonary Hemodynamics ◽  
Hypoxic Pulmonary Hypertension ◽  
Significant Difference

Angiogenic factors exert protective effects on the lung. To investigate the effect of VEGF-B, a factor coexpressed in the lung with VEGF-A, we assessed chronic hypoxic pulmonary hypertension in VEGF-B knockout mice (VEGF-B−/−) and in rats with lung overexpression of VEGF-B induced by adenovirus transfer. No significant difference in pulmonary hemodynamics, right ventricular hypertrophy, distal vessel muscularization, or vascular density was found between VEGF-B−/− and control mice after 3 wk of hypoxia. When overexpressed, VEGF-B167 or VEGF-B186 had protective effects similar to those of human VEGF-A165. Lung endothelial nitric oxide synthase (eNOS) expression was increased by 5 days of hypoxia or VEGF-A adenovirus vector (Ad.VEGF-A) overexpression, whereas VEGF-B167 or VEGF-B186had no effect. With hypoxia or normoxia, the wet-to-dry lung weight ratio was increased 5 days after Ad.VEGF-A administration compared with control (Ad.nul), Ad.VEGF-B167, or Ad.VEGF-B186. Endogenous VEGF-B does not counteract the development of hypoxic pulmonary hypertension. However, when overexpressed in the lung, VEGF-B can be as potent as VEGF-A in attenuating pulmonary hypertension, although it has no effect on eNOS expression or vascular permeability.

Neutral endopeptidase inhibition attenuates development of hypoxic pulmonary hypertension in rats

1993 ◽  
Vol 75 (4) ◽  
pp. 1615-1623 ◽  
Author(s):  
J. R. Klinger ◽  
R. D. Petit ◽  
R. R. Warburton ◽  
D. S. Wrenn ◽  
F. Arnal ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Pulmonary Arteries ◽  
Systolic Pressure ◽  
Weight Ratio ◽  
Neutral Endopeptidase ◽  
Mrna Levels ◽  
Hypoxic Pulmonary Hypertension ◽  
Ventricular Systolic Pressure ◽  
Nep Inhibition

Neutral endopeptidase (NEP) inhibition is thought to blunt hypoxic pulmonary hypertension by reducing atrial natriuretic peptide (ANP) metabolism, but this hypothesis has not been confirmed. We measured NEP activity, guanosine 3',5'-cyclic monophosphate (cGMP) production, plasma ANP levels, and cardiac ANP synthesis in rats given an orally active NEP inhibitor (SCH-34826) during 3 wk of hypoxia. Under normoxic conditions, SCH-34826 had no effect on plasma ANP levels but reduced pulmonary and renal NEP activity by 50% and increased urinary cGMP levels (60 +/- 6 vs. 22 +/- 4 pg/mg creatinine; P < 0.05). Under hypoxic conditions, SCH-34826-treated rats had lower plasma ANP levels (1,259 +/- 361 vs. 2,101 +/- 278 pg/ml; P < 0.05), lower right ventricular systolic pressure (53 +/- 5 vs. 73 +/- 2 mmHg; P < 0.05), lower right ventricle weight-to-left ventricle+septum weight ratio (0.47 +/- 0.04 vs. 0.53 +/- 0.03; P < 0.05), and less muscularization and percent medial wall thickness of peripheral pulmonary arteries (22 +/- 5 vs. 45 +/- 8% and 17 +/- 1 vs. 25 +/- 1%, respectively; P < 0.05 for all values) than did rats treated with vehicle alone. These values were not affected by SCH-34826 under normoxic conditions. SCH-34826 decreased right ventricular ANP tissue levels in hypoxic rats (27 +/- 10 vs. 8 +/- 1 ng/mg protein; P < 0.05) but did not affect steady-state ANP mRNA levels. We conclude that NEP inhibition blunts pulmonary hypertension without increasing plasma ANP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Punicalagin Prevents Hypoxic Pulmonary Hypertension via Anti-Oxidant Effects in Rats

2016 ◽  
Vol 44 (04) ◽  
pp. 785-801 ◽  
Author(s):  
Jingyun Shao ◽  
Peng Wang ◽  
An Liu ◽  
Xusheng Du ◽  
Jie Bai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Pulmonary Arteries ◽  
Pomegranate Juice ◽  
No Production ◽  
Protective Effects ◽  
Hypoxic Pulmonary Hypertension ◽  
Beneficial Effects ◽  
Anti Oxidant

Punicalagin (PG), a major bioactive ingredient in pomegranate juice, has been proven to have anti-oxidative stress properties and to exert protective effects on acute lung injuries induced by lipopolysaccharides. This study aimed to investigate the effects of PG treatment on hypoxic pulmonary hypertension (HPH) and the underlying mechanisms responsible for the effects. Rats were exposed to 10% oxygen for 2 wk (8 h/day) to induce the HPH model. PG (5, 15, 45[Formula: see text]mg/kg) was orally administered 10[Formula: see text]min before hypoxia each day. PG treatments at the doses of 15 and 45[Formula: see text]mg/kg/d decreased the mean pulmonary arterial pressure (mPAP) and alleviated right ventricular hypertrophy and vascular remodeling in HPH rats. Meanwhile, PG treatment attenuated the hypoxia-induced endothelial dysfunction of pulmonary artery rings. The beneficial effects of PG treatment were associated with improved nitric oxide (NO)-cGMP signaling and reduced oxidative stress, as evidenced by decreased superoxide generation, gp91[Formula: see text] expression and nitrotyrosine content in the pulmonary arteries. Furthermore, tempol’s scavenging of oxidative stress also increased NO production and attenuated endothelial dysfunction and pulmonary hypertension in HPH rats. Combining tempol and PG did not exert additional beneficial effects compared to tempol alone. Our study indicated for the first time that PG treatment can protect against hypoxia-induced endothelial dysfunction and pulmonary hypertension in rats, which may be induced via its anti-oxidant actions.

The Effect of Left Ventricular Assist Device Therapy in Patients with Heart Failure and Mixed Pulmonary Hypertension

2017 ◽  
Vol 40 (2) ◽  
pp. 67-73 ◽  
Author(s):  
Hoong S. Lim ◽  
Neil Howell ◽  
Aaron Ranasinghe
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Pulmonary Hypertension ◽  
Left Ventricular ◽  
Ventricular Assist Devices ◽  
Right Atrial ◽  
Pulmonary Hemodynamics ◽  
Ventricular Assist ◽  
Significant Difference ◽  
Left Ventricular Assist

Background Diastolic pressure gradient (DPG) of ≥7 mmHg has been proposed to distinguish mixed pulmonary hypertension from isolated post-capillary pulmonary hypertension in heart failure (HF). We evaluated the changes in pulmonary hemodynamics with left ventricular assist devices (LVADs) in patients with DPG of ≥7 or <7 mmHg, and effects on peak oxygen uptake (VO2) in patients with advanced HF. Methods Pre- and post-LVAD implant pulmonary hemodynamics (including right atrial (RA) pressures, DPG, pulmonary vascular resistance (PVR), pulmonary capacitance (PCap) and cardiac output), echocardiography, cardiopulmonary exercise test were measured in 38 consecutive patients. Results Ten of 38 patients had baseline DPG ≥7 mmHg. There were no significant difference in baseline characteristics, peak VO2 and ventilation slope, but PVR were higher, and PCap lower in patients with DPG ≥7 mmHg. Pulmonary artery pressures improved in all patients, but PVR and DPG remained higher and PCap lower in patients with baseline DPG ≥7 mmHg after a median follow-up of 181 (IQR 153–193) days. Peak VO2 increased and ventilation slope reduced post-LVAD, and these improvements were comparable between groups. Only RA pressure reduction and exercise increase in heart rate were significant predictors of peak VO2 increase on multivariate analysis. Conclusions Baseline DPG of ≥7 mmHg compared to DPG <7 mmHg have persistently lower PCap and higher PVR post-LVAD, but the increase in peak VO2 was comparable despite these residual pulmonary vascular abnormalities. The improvement in peak VO2 was related to reduction in right atrial pressure and exercise increase in heart rate.

scholarly journals Ghrelin ameliorates hypoxia-induced pulmonary hypertension via phospho-GSK3β/β-catenin signaling in neonatal rats

2011 ◽  
Vol 47 (1) ◽  
pp. 33-43 ◽  
Author(s):  
Yan-ping Xu ◽  
Jia-jun Zhu ◽  
Fen Cheng ◽  
Ke-wen Jiang ◽  
Wei-zhong Gu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Effective Treatment ◽  
Glycogen Synthase ◽  
Weight Ratio ◽  
Molecular Signaling ◽  
Neonatal Rats ◽  
Growth Hormone Secretagogue Receptor ◽  
Pulmonary Hemodynamics ◽  
Growth Hormone Secretagogue ◽  
Beneficial Effects

Effective treatment and/or prevention strategies for neonatal persistent pulmonary hypertension of the newborn (PPHN) have been an important topic in neonatal medicine. However, mechanisms of impaired pulmonary vascular structure in hypoxia-induced PPHN are poorly understood and consequently limit the development of effective treatment. In this study, we aimed to explore the molecular signaling cascades in the lungs of a PPHN animal model and used primary cultured rat pulmonary microvascular endothelial cells to analyze the physiological benefits of ghrelin during the pathogenesis of PPHN. Randomly selected newborn rats were exposed to hypoxia (10–12%) or room air and received daily s.c. injections of ghrelin (150 μg/kg) or saline. After 2 weeks, pulmonary hemodynamics and morphometry were assessed in the rats. Compared with the control, hypoxia increased pulmonary arterial pressure, right ventricle (RV) hypertrophy, and arteriolar wall thickness. Ghrelin treatment reduced both the magnitude of PH and the RV/(left ventricle+septum (Sep)) weight ratio. Ghrelin protected neonatal rats from hypoxia-induced PH via the upregulation of phosphorylation of glycogen synthase kinase 3β (p-GSK3β)/β-catenin signaling and associated with β-catenin translocation to the nucleus in the presence of growth hormone secretagogue receptor-1a. Our findings suggest that s.c. administration of ghrelin improved PH and attenuated pulmonary vascular remodeling after PPHN. These beneficial effects may be mediated by the regulation of p-GSK3β/β-catenin expression. We propose ghrelin as a novel potential therapeutic agent for PPHN.

Role of angiotensin-converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension

1995 ◽  
Vol 269 (4) ◽  
pp. H1186-H1194 ◽  
Author(s):  
N. W. Morrell ◽  
K. G. Morris ◽  
K. R. Stenmark
Keyword(s):  
Pulmonary Hypertension ◽  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Vascular Remodeling ◽  
Ace Inhibition ◽  
Protective Effects ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Hypoxic Pulmonary Hypertension

Although angiotensin converting enzyme (ACE) inhibitors are known to attenuate the development of hypoxic pulmonary hypertension in rats, the precise mechanism of this protective effect remains unknown. Thus we utilized specific angiotensin II (ANG II)-receptor antagonists to investigate whether ANG II is involved directly in the hemodynamic and structural changes of pulmonary hypertension, and we tested whether the protective effects of ACE inhibition can be attributed partly to potentiation of bradykinin. During 14 days of hypobaric hypoxia, rats received, via intraperitoneal osmotic minipumps, either 1) the ACE inhibitor captopril, 2) captopril plus the bradykinin B2-receptor antagonist CP-0597, 3) the ANG II type 1 receptor antagonist losartan, 4) the ANG II type 2 receptor antagonist PD-123319, or 5) saline. At 14 days, mean pulmonary arterial pressure (MPAP) was reduced (P < 0.05) in hypoxic rats treated with captopril (26.6 +/- 0.8 mmHg) or losartan (24.4 +/- 1.0 mmHg) compared with saline (32.0 +/- 1.4 mmHg) but was unaffected by PD-123319 (29.5 +/- 1.7 mmHg). Right ventricular hypertrophy was reduced in hypoxic rats treated with captopril or losartan compared with saline-treated rats. Morphometry showed less medial thickening and peripheral muscularization of small pulmonary arteries in hypoxic animals treated with captopril or losartan. Coadministration of CP-0597 did not reverse the protective effects of captopril on pulmonary vascular remodeling. These results suggest a novel role for endogenous ANG II, acting through the type 1 receptor, in the vascular remodeling associated with hypoxic pulmonary hypertension. The beneficial effects of ACE inhibition in this model can be attributed to reduced ANG II production rather than potentiation of bradykinin.

scholarly journals The Protective Effects of Κ-Opioid Receptor Stimulation in Hypoxic Pulmonary Hypertension Involve Inhibition of Autophagy Through the AMPK-MTOR Pathway

2017 ◽  
Vol 44 (5) ◽  
pp. 1965-1979 ◽  
Author(s):  
Yaguang Zhou ◽  
Yuanbo Wang ◽  
Xu Wang ◽  
Xin Tian ◽  
Shumiao Zhang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Western Blot ◽  
Opioid Receptor ◽  
Mtor Pathway ◽  
Cell Counting ◽  
Protective Effects ◽  
Receptor Stimulation ◽  
Hypoxic Pulmonary Hypertension ◽  
Pulmonary Arterial

Background/Aims: In a previous study, we showed that κ-opioid receptor stimulation with the selective agonist U50,488H ameliorated hypoxic pulmonary hypertension (HPH). However, the roles that pulmonary arterial smooth muscle cell (PASMC) proliferation, apoptosis, and autophagy play in κ-opioid receptor-mediated protection against HPH are still unknown. The goal of the present study was to investigate the role of autophagy in U50,488H-induced HPH protection and the underlying mechanisms. Methods: Rats were exposed to 10% oxygen for three weeks to induce HPH. After hypoxia, the mean pulmonary arterial pressure (mPAP) and the right ventricular pressure (RVP) were measured. Cell viability was monitored using the Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis was detected by flow cytometry and Western blot. Autophagy was assessed by means of the mRFP-GFP-LC3 adenovirus transfection assay and by Western blot. Results: Inhibition of autophagy by the administration of chloroquine prevented the development of HPH in the rat model, as evidenced by significantly reduced mPAP and RVP, as well as decreased autophagy. U50,488H mimicked the effects of chloroquine, and the effects of U50,488H were blocked by nor-BNI, a selective κ-opioid receptor antagonist. In vitro experiments showed that the inhibition of autophagy by chloroquine was associated with decreased proliferation and increased apoptosis of PASMCs. Under hypoxia, U50,488H also significantly inhibited autophagy, reduced proliferation and increased apoptosis of PASMCs. These effects of U50,488H were blocked by nor-BNI. Moreover, exposure to hypoxic conditions significantly increased AMPK phosphorylation and reduced mTOR phosphorylation, and these effects were abrogated by U50,488H. The effects of U50,488H on PASMC autophagy were inhibited by AICAR, a selective AMPK agonist, or by rapamycin, a selective mTOR inhibitor. Conclusion: Our data provide evidence for the first time that κ-opioid receptor stimulation protects against HPH by inhibiting PASMCs autophagy via the AMPK-mTOR pathway.

Role of venoconstriction in thromboxane-induced pulmonary hypertension and edema in lambs

1989 ◽  
Vol 66 (2) ◽  
pp. 929-935 ◽  
Author(s):  
K. Yoshimura ◽  
M. L. Tod ◽  
K. G. Pier ◽  
L. J. Rubin
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Edema ◽  
Weight Ratio ◽  
Primary Component ◽  
Pressure Gradients ◽  
Lung Weight ◽  
Pressure Drops ◽  
Occlusion Technique ◽  
Pulmonary Arterial

We evaluated the dose response to a stable thromboxane (Tx) A2 analogue (sTxA2; 0.3–30 micrograms) in the pulmonary circulation and its effect on the distribution of pressure gradients determined by the occlusion technique in isolated nonblood perfused newborn lamb lungs. The total pulmonary pressure gradient (delta Pt) was partitioned into pressure drops across the relatively indistensible arteries and veins (delta Pv) and relatively compliant vessels. We also evaluated the effects of prostacyclin (PGI2) and a Tx receptor antagonist (ONO 3708) on the sTxA2-induced pulmonary responses. Injection of sTxA2 caused a dose-related increase in the pulmonary arterial pressure, with the primary component of the increase in delta Pt (4.1 +/- 0.8 to 13.9 +/- 0.4 Torr) at 30 micrograms derived from the prominent rise in delta Pv (1.8 +/- 0.3 to 9.8 +/- 0.9 Torr). Infusion of PGI2 (0.4 microgram.kg-1.min-1) reduced the response to sTxA2 mainly by attenuating the delta Pv elevation. Infusion of ONO 3708 (100 micrograms.kg-1.min-1) completely abolished the sTxA2-induced pulmonary hypertension. Injection of sTxA2 resulted in pulmonary edema characterized by a significant increase in wet-to-dry lung weight ratio (9.13 +/- 0.35 vs. 7.15 +/- 0.41 in control lungs). The sTxA2-induced pulmonary edema was increased by PGI2 and inhibited by ONO 3708. We conclude that thromboxane-induced pulmonary hypertension is primarily produced by venoconstriction and prostacyclin may worsen the edema induced by thromboxane.

scholarly journals Biopterin Metabolism and eNOS Expression during Hypoxic Pulmonary Hypertension in Mice

PLoS ONE ◽  
2013 ◽  
Vol 8 (11) ◽  
pp. e82594 ◽  
Author(s):  
Mathilde Dubois ◽  
Estelle Delannoy ◽  
Lucie Duluc ◽  
Ellen Closs ◽  
Huige Li ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Enos Expression ◽  
Hypoxic Pulmonary Hypertension

scholarly journals Overexpression of YAP and miR-130a is closely related to pulmonary hypertension in congenital diaphragmatic hernia

2020 ◽  
Vol 185 ◽  
pp. 03003
Author(s):  
Junzuo Liao ◽  
Wenying Liu ◽  
Libin Zhang ◽  
Qin Li ◽  
Fang Hou
Keyword(s):  
Pulmonary Hypertension ◽  
Relative Increase ◽  
Feedback Mechanism ◽  
Female Rats ◽  
Normal Lung ◽  
Control Group ◽  
Lung Weight ◽  
Pregnant Rats ◽  
Significant Difference

Purpose: The aim of this study was to investigate the expression of YAP and miR-130a in the normal lung tissues and CDH lung tissues through the rat model of CDH, and preliminarily explored the relationship between YAP, miR-130a and CDH. Methods: Pregnant rats were divided into two groups: control (n = 5) and CDH (n = 5). A single oral dose (125 mg/kg) of nitrofen was administered to pregnant rats on embryonic day (E) 9.5 to induce CDH. All fetuses were acquired by cesarean delivery on E21.5. Fetuses with diaphragmatic hernias in the CDH groups were chosen for analysis. Lung weight (LW) and body weight (BW) were recorded and histologic evaluations, image analysis, western blot analysis and PCR were performed after lung processing. Results: Five female rats in the control group produced 76 fetuses without CDH. CDH was observed in 49 of 72 rat fetuses in the CDH group. Pulmonary hypoplasia and vascular remodeling were observed in the CDH group. YAP expression in the lungs was markedly increased in the CDH group compared to the control group (P = 0.001). However, there was no significant difference in the phosphorylation level of YAP (P = 0.113) between the two group. YAP mRNA and miR-130a expression in the lungs were markedly increased in the CDH group compared to the control group (P = 0.01, P = 0.002). Conclusion: A relative increase YAP activity and miR-130a expression in the CDH rats may be associated with increased pulmonary vascular resistance. The role of the feedback mechanism between YAP and miR-130a playing in the CDH-associated pulmonary hypertension deserves further study.

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