Vascular growth and remodeling in compensatory lung growth following right lobectomy

2005 ◽  
Vol 98 (3) ◽  
pp. 1140-1148 ◽  
Author(s):  
Timothy D. Le Cras ◽  
Lucas G. Fernandez ◽  
Patricia A. Pastura ◽  
Victor E. Laubach
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Pulmonary Arteries ◽  
Left Lung ◽  
Lung Mass ◽  
Growth And Remodeling ◽  
Adult Rats ◽  
Vascular Growth

Studies in animal models have shown that, following lobectomy (LBX), there is compensatory growth in the remaining lung. The vascular growth response following right LBX (R-LBX) is poorly understood. To test the hypothesis that arterial growth and remodeling occur in response to LBX, in proportion to the amount of right lung tissue removed, two (24% of lung mass; R-LBX2 group) or three right lobes (52% of lung mass; R-LBX3 group) were removed via thoracotomy from adult rats. Sham control animals underwent thoracotomy only. Arteriograms were generated 3 wk after surgery. The areas of the left lung arteriogram, arterial branching, length of arterial branches, arterial density, and arterial-to-alveolar ratios were measured. To determine whether R-LBX causes vascular remodeling and pulmonary hypertension, muscularization of arterioles and right ventricular hypertrophy were assessed. Lung weight and volume indexes were greater in R-LBX3. Arterial area of the left lung increased 26% in R-LBX2 and 47% in R-LBX3. The length of large arteries increased in R-LBX3 and to a lesser extent in R-LBX2. The ratio of distal pulmonary arteries to alveoli was similar after R-LBX2 compared with sham but was 30% lower in R-LBX3. Muscularization of arterioles increased after R-LBX3, but not in R-LBX2. Right ventricular hypertrophy increased 50–70% in R-LBX3, but not in R-LBX2. Whereas removal of three right lung lobes induced arterial growth in the left lungs of adult rats, which was proportionate to the number of lobes removed, the ratio of distal pulmonary arteries to alveoli was not normal, and vascular remodeling and pulmonary hypertension developed.

Abstract 622: Cd44 Plays an Important Role in Regulating Heart Failure Induced Lung Vascular Remodeling and Who Type-2 Pulmonary Hypertension

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Xinyu Weng ◽  
Wenhui Yue ◽  
Dongzhi Wang ◽  
Huan Wang ◽  
Yawei Xu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Lung Inflammation ◽  
Ventricular Hypertrophy ◽  
Left Ventricular ◽  
Left Ventricular Failure ◽  
Ventricular Failure

End-stage left ventricular failure or chronic heart failure (CHF) causes severe lung inflammation, vascular remodeling, WHO type-2 pulmonary hypertension, and right ventricular hypertrophy. However, the molecular mechanism of CHF-induced lung inflammation and remodeling is largely unknown. CD44 is a member of the hyaluronate receptor family of cell adhesion molecules, which has been shown to play a selective role in controlling macrophage and lymphocyte migration. Here we demonstrated that end-stage CHF causes a dramatic increase of CD44 expression in heart and lung in human and mice. Histological staining shows that CD44 is predominantly expressed in leukocytes such as macrophages. Flow cytometry analysis further demonstrates that CD44 is predominantly expressed in F4/80 positive macrophages, CD4+, and CD8+ T cells. CD44 expression is dramatically increased in activated T cell subsets. To further determine the physiological role of CD44 in CHF-induced lung remodeling and type-2 pulmonary hypertension, we studied the effect of CD44 blockade on type-2 pulmonary hypertension development in a group of mice with existing moderate left ventricular failure without apparent lung remodeling. Interestingly, we found that blockade CD44 with blocking antibodies (Abs) significantly attenuate the development of lung vascular and interstitial leukocyte infiltration, lung vascular remodeling, fibrosis, and increase of right ventricular hypertrophy. Blockade CD44 signaling also significantly attenuated further decline of left ventricular ejection fraction in mice with existing LV failure. In addition, we demonstrated that induction of T regulatory cells with IL-2 and IL-2 Abs complex significantly attenuated the infiltration of CD44 positive leukocytes in lung tissue, lung vascular remodeling, lung fibrosis, and right ventricular hypertrophy in mice with existing moderate left ventricular failure. Together, these data indicate an important role of CD44 in left ventricular failure-induced lung inflammation, and type-2 pulmonary hypertension, suggesting that inhibition of CD44 may attenuate heart failure progression and type-2 pulmonary hypertension.

p53 Gene deficiency promotes hypoxia-induced pulmonary hypertension and vascular remodeling in mice

2011 ◽  
Vol 300 (5) ◽  
pp. L753-L761 ◽  
Author(s):  
Shiro Mizuno ◽  
Herman J. Bogaard ◽  
Donatas Kraskauskas ◽  
Aysar Alhussaini ◽  
Jose Gomez-Arroyo ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Left Ventricle ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Hypoxic Exposure ◽  
Arterial Remodeling ◽  
Pulmonary Arterial ◽  
The Right

Chronic hypoxia induces pulmonary arterial remodeling, resulting in pulmonary hypertension and right ventricular hypertrophy. Hypoxia has been implicated as a physiological stimulus for p53 induction and hypoxia-inducible factor-1α (HIF-1α). However, the subcellular interactions between hypoxic exposure and expression of p53 and HIF-1α remain unclear. To examine the role of p53 and HIF-1α expression on hypoxia-induced pulmonary arterial remodeling, wild-type (WT) and p53 knockout (p53KO) mice were exposed to either normoxia or hypoxia for 8 wk. Following chronic hypoxia, both genotypes demonstrated elevated right ventricular pressures, right ventricular hypertrophy as measured by the ratio of the right ventricle to the left ventricle plus septum weights, and vascular remodeling. However, the right ventricular systolic pressures, the ratio of the right ventricle to the left ventricle plus septum weights, and the medial wall thickness of small vessels were significantly greater in the p53KO mice than in the WT mice. The p53KO mice had lower levels of p21 and miR34a expression, and higher levels of HIF-1α, VEGF, and PDGF expression than WT mice following chronic hypoxic exposure. This was associated with a higher proliferating cell nuclear antigen expression of pulmonary artery in p53KO mice. We conclude that p53 plays a critical role in the mitigation of hypoxia-induced small pulmonary arterial remodeling. By interacting with p21 and HIF-1α, p53 may suppress hypoxic pulmonary arterial remodeling and pulmonary arterial smooth muscle cell proliferation under hypoxia.

Granulocyte colony-stimulating factor enhances alpha-naphthylthiourea-induced pulmonary hypertension

2003 ◽  
Vol 94 (5) ◽  
pp. 2027-2033 ◽  
Author(s):  
Élie Azoulay ◽  
Saadia Eddahibi ◽  
Élisabeth Marcos ◽  
Micheline Levame ◽  
Alain Harf ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Vascular Endothelial Cell ◽  
Right Ventricular Hypertrophy ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Underlying Mechanisms ◽  
Stimulating Factor

Physiopathological discrepancies exist between the most widely used models of pulmonary hypertension (PH), namely monocrotaline- and hypoxia-induced PH. The development of a new model could help in the understanding of underlying mechanisms. Repeated alpha-naphthylthiourea (ANTU) injections (5 mg/kg weekly, 3 wk) induced pulmonary vascular remodeling, which was associated with development of PH and right ventricular hypertrophy. ANTU followed by granulocyte colony-stimulating factor (G-CSF; 25 μg · kg−1 · day−1subcutaneously, 3 days/wk) induced higher pulmonary arterial pressures and right ventricular hypertrophy than ANTU alone. Lidocaine, which inhibits neutrophil functions, inhibited PH exacerbation by G-CSF. Endothelial nitric oxide synthase expression, measured to assess ANTU-related endothelial toxicity, decreased significantly in ANTU-treated rats and fell even more sharply when G-CSF was given. This occurred despite a significant increase in vascular endothelial cell growth factor expression in lung and right ventricle in rats given ANTU alone and even more in rats given ANTU plus G-CSF. Repeated ANTU administration induces PH with vascular remodeling that can be further aggravated by the neutrophil activator G-CSF.

scholarly journals NFATc3 is required for chronic hypoxia-induced pulmonary hypertension in adult and neonatal mice

2011 ◽  
Vol 301 (6) ◽  
pp. L872-L880 ◽  
Author(s):  
R. Bierer ◽  
C. H. Nitta ◽  
J. Friedman ◽  
S. Codianni ◽  
S. de Frutos ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Systolic Pressure ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Neonatal Mice ◽  
Adult Mice

Pulmonary hypertension occurs with prolonged exposure to chronic hypoxia in both adults and neonates. The Ca2+-dependent transcription factor, nuclear factor of activated T cells isoform c3 (NFATc3), has been implicated in chronic hypoxia-induced pulmonary arterial remodeling in adult mice. Therefore, we hypothesized that NFATc3 is required for chronic hypoxia-induced pulmonary hypertension in adult and neonatal mice. The aim of this study was to determine whether 1) NFATc3 mediates chronic hypoxia-induced increases in right ventricular systolic pressure in adult mice; 2) NFATc3 is activated in neonatal mice exposed to chronic hypoxia; and 3) NFATc3 is involved in chronic hypoxia-induced right ventricular hypertrophy and pulmonary vascular remodeling in neonatal mice. Adult mice were exposed to hypobaric hypoxia for 2, 7, and 21 days. Neonatal mouse pups were exposed for 7 days to hypobaric chronic hypoxia within 2 days after delivery. Hypoxia-induced increases in right ventricular systolic pressure were absent in NFATc3 knockout adult mice. In neonatal mice, chronic hypoxia caused NFAT activation in whole lung and nuclear accumulation of NFATc3 in both pulmonary vascular smooth muscle and endothelial cells. In addition, heterozygous NFATc3 neonates showed less right ventricular hypertrophy and pulmonary artery wall thickness in response to chronic hypoxia than did wild-type neonates. Our results suggest that NFATc3 mediates pulmonary hypertension and vascular remodeling in both adult and neonatal mice.

α1-Adrenoceptor-dependent vascular hypertrophy and remodeling in murine hypoxic pulmonary hypertension

2007 ◽  
Vol 292 (5) ◽  
pp. H2316-H2323 ◽  
Author(s):  
James E. Faber ◽  
Caroline L. Szymeczek ◽  
Susanna Cotecchia ◽  
Steven A. Thomas ◽  
Akito Tanoue ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Pulmonary Arteries ◽  
Vascular Wall ◽  
Ventricular Pressure ◽  
Hypoxic Pulmonary Hypertension ◽  
Oxygen Fraction ◽  
Stimulation Of

Excessive proliferation of vascular wall cells underlies the development of elevated vascular resistance in hypoxic pulmonary hypertension (PH), but the responsible mechanisms remain unclear. Growth-promoting effects of catecholamines may contribute. Hypoxemia causes sympathoexcitation, and prolonged stimulation of α1-adrenoceptors (α1-ARs) induces hypertrophy and hyperplasia of arterial smooth muscle cells and adventitial fibroblasts. Catecholamine trophic actions in arteries are enhanced when other conditions favoring growth or remodeling are present, e.g., injury or altered shear stress, in isolated pulmonary arteries from rats with hypoxic PH. The present study examined the hypothesis that catecholamines contribute to pulmonary vascular remodeling in vivo in hypoxic PH. Mice genetically deficient in norepinephrine and epinephrine production [dopamine β-hydroxylase−/− (DBH−/−)] or α1-ARs were examined for alterations in PH, cardiac hypertrophy, and vascular remodeling after 21 days exposure to normobaric 0.1 inspired oxygen fraction (FiO2). A decrease in the lumen area and an increase in the wall thickness of arteries were strongly inhibited in knockout mice (order of extent of inhibition: DBH−/− = α1D-AR−/− > α1B-AR−/−). Distal muscularization of small arterioles was also reduced (DBH−/− > α1D-AR−/− > α1B-AR−/− mice). Despite these reductions, increases in right ventricular pressure and hypertrophy were not attenuated in DBH−/− and α1B-AR−/− mice. However, hematocrit increased more in these mice, possibly as a consequence of impaired cardiovascular activation that occurs during reduction of FiO2. In contrast, in α1D-AR−/− mice, where hematocrit increased the same as in wild-type mice, right ventricular pressure was reduced. These data suggest that catecholamine stimulation of α1B- and α1D-ARs contributes significantly to vascular remodeling in hypoxic PH.

scholarly journals Differential Expression of Three Hypoxia-inducible Factor-α Subunits in Pulmonary Arteries of Rat with Hypoxia-induced Hypertension

2005 ◽  
Vol 37 (10) ◽  
pp. 665-672 ◽  
Author(s):  
Qi-Fang Li ◽  
Ai-Guo Dai
Keyword(s):  
Pulmonary Hypertension ◽  
Western Blot ◽  
Right Ventricular ◽  
Ventricular Hypertrophy ◽  
Target Genes ◽  
Expression Patterns ◽  
Pulmonary Arteries ◽  
Right Ventricular Hypertrophy ◽  
Mrna Levels ◽  
Α Subunits

AbstractHypoxia inducible transcription factor (HIF)-1α plays an important role in the development of hypoxic pulmonary hypertension, but little is known about HIF-2α and HIF-3α with respect to transcriptional regulation by hypoxia. To examine the expression patterns of all HIF-α subunits (HIF-1α, HIF-2α and HIF-3α) in pulmonary arteries of rats undergoing systemic hypoxia, five groups of healthy male Wistar rats were exposed to normoxia (N) and hypoxia for 3 (H3), 7 (H7), 14 (H14) and 21 (H21) d respectively. Mean pulmonary arterial pressure (mPAP), vessel morphometry and right ventricular hypertrophy index were measured. Lungs were inflation fixed for immunohistochemistry and in situ hybridization, and homogenized for Western blot. mPAP increased significantly after 7 d of hypoxia [(18.4±0.4) vs. (14.4±0.4) mmHg, H7 vs. N], reached its peak after 14 d of hypoxia, then remained stable. Pulmonary artery remodeling and right ventricular hypertrophy developed significantly after 14 d of hypoxia. During normoxia, HIF-1α and HIF-3α staining were slightly positive regarding mRNA levels. A substantial alteration of HIF-1α and HIF-3α staining occurred in pulmonary arteries after 14 d and 7 d of hypoxia, respectively, but HIF-2α staining showed an inversed trend after 14 d of hypoxia. Protein levels of all HIF-α subunits except HIF-3α showed a marked increase corresponding to the duration of hypoxia, which was obtained by Western blot. Our study found that HIF-1α, HIF-2α and HIF-3α may not only confer different target genes, but also play key pathogenetic roles in hypoxic-induced pulmonary hypertension.

ETA-receptor antagonist prevents and reverses chronic hypoxia-induced pulmonary hypertension in rat

1995 ◽  
Vol 269 (5) ◽  
pp. L690-L697 ◽  
Author(s):  
V. S. DiCarlo ◽  
S. J. Chen ◽  
Q. C. Meng ◽  
J. Durand ◽  
M. Yano ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Receptor Antagonist ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Vascular Remodeling ◽  
Eta Receptor ◽  
Eta Receptor Antagonist

The selective endothelin-A (ETA)-receptor antagonist BQ-123 has been shown to prevent chronic hypoxia-induced pulmonary hypertension in the rat. Therefore in the current study we utilized BQ-123 to test the hypothesis that blockade of the ETA receptor can reverse as well as prevent the increase in mean pulmonary artery pressure, right ventricle-to-left ventricle plus septum ratio, and percent wall thickness in small (50-100 microns) pulmonary arteries observed in male Sprague-Dawley rats exposed to normobaric hypoxia (10% O2, 2 wk). Infusion of BQ-123 (0.4 mg.0.5 microliter-1.h-1 for 2 wk in 10% O2) begun after 2 wk of hypoxia significantly reversed the established pulmonary hypertension and prevented further progression of right ventricular hypertrophy during the third and fourth week of hypoxia. BQ-123 infusion instituted before exposure to hypoxia completely prevented the hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling. These findings suggest that, in the lung, hypoxia induced an increase synthesis of endothelin-1, which acts locally on ETA receptors to cause pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling, while ETA-receptor blockade can both prevent and reverse these processes.

PRIMARY PULMONARY HYPERTENSION

PEDIATRICS ◽  
1957 ◽  
Vol 20 (3) ◽  
pp. 408-415
Author(s):  
Harvey S. Rosenberg ◽  
Dan G. McNamara
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Ventricular Hypertrophy ◽  
Primary Pulmonary Hypertension ◽  
Pulmonary Arteries ◽  
Right Ventricular Hypertrophy ◽  
Vascular Change ◽  
Progressive Dyspnea ◽  
Peripheral Lung ◽  
Secondary Pulmonary Hypertension

A case is reported of a 4-month-old infant in which the outstanding clinical features were failure to gain weight, cough, and progressive dyspnea. There was marked accentuation of the second pulmonic sound and no significant murmur. The electrocardiogram was interpreted as showing right ventricular hypertrophy and roentgenographically, there was unusual clarity of peripheral lung fields and prominence of hilar vessels. Cardiac catheterization demonstrated pulmonary hypertension and revealed no left to right intracardiac shunt. Anatomically, there was right ventricular hypertrophy and prominence of the medial layer of the small pulmonary arteries. This vascular change is indistinguishable from that seen in the normal newborn and certain varieties of secondary pulmonary hypertension. Although the clinical diagnosis can be suspected, the definitive anomaly can be determined only at post-mortem examination.

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