scholarly journals The Role of Collagen Synthesis in Ventricular and Vascular Adaptation to Hypoxic Pulmonary Hypertension

2012 ◽  
Author(s):  
David Schreier ◽  
Timothy Hacker ◽  
Guoqing Song ◽  
Naomi Chesler
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Collagen Synthesis ◽  
Pulmonary Arteries ◽  
Hypoxic Pulmonary Hypertension ◽  
Arterial Stiffening ◽  
Vascular Adaptation ◽  
Small Vessels ◽  
Effects Of Ph

Pulmonary hypertension (PH) is a debilitating disease that affects millions of Americans. Most research to date has focused on the deleterious effects of PH within the small vessels of the lungs that determine resistance. A relatively recent focus of PH is on the large pulmonary arteries (PAs) that provide compliance. Loss of compliance in these arteries, or arterial stiffening, is an excellent predictor of mortality in PH [1], which is most often caused by right ventricular (RV) hypertrophy and failure [2].

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)

Possible role of pulmonary blood volume in chronic hypoxic pulmonary hypertension

1993 ◽  
Vol 74 (6) ◽  
pp. 3020-3026 ◽  
Author(s):  
L. C. Ou ◽  
G. L. Sardella ◽  
N. S. Hill ◽  
C. D. Thron
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Blood Volume ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Right Ventricular Hypertrophy ◽  
Hypoxic Pulmonary Hypertension ◽  
Pulmonary Blood Volume

Chronic hypoxia increases the total blood volume (TBV) and pulmonary arterial blood pressure (Ppa) and induces pulmonary vascular remodeling. The present study was undertaken to assess how the pulmonary blood volume (PBV) changes during hypoxia and the possible role of PBV in chronic hypoxic pulmonary hypertension. A novel method has been developed to measure the TBV, PBV, and Ppa in conscious rats. The method consists of chronic implantation of a loose ligature around the ascending aorta and pulmonary artery, so that when the ligature is drawn tightly, it traps the blood in the pulmonary vessels and left heart and simultaneously kills the rat. The pulmonary veins are then ligated to separate the left ventricular blood volume from the PBV. This surgical approach, together with chronic catheterization of the pulmonary artery and the use of 51Cr-labeled red blood cells, allows measurement of TBV, PBV, and Ppa. This method has been used to analyze the relationships between TBV and PBV and between Ppa or right ventricular hypertrophy and PBV in two rat strains with markedly different TBV and Ppa responses to chronic hypoxia. PBV per given lung weight did not increase and even decreased during hypoxia despite marked increases in TBV. There was a close correlation between Ppa or right ventricular hypertrophy and PBV in the two strains of chronically hypoxic animals, suggesting that a greater PBV plays a significant role in the development of severe chronic hypoxic pulmonary hypertension in the altitude-susceptible Hilltop rats.

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 Lung Mast Cells and Hypoxic Pulmonary Hypertension

2012 ◽  
pp. 1-11 ◽  
Author(s):  
H. MAXOVÁ ◽  
J. HERGET ◽  
M. VÍZEK
Keyword(s):  
Pulmonary Hypertension ◽  
Mast Cells ◽  
Cell Activation ◽  
Proteolytic Enzymes ◽  
Inflammatory Diseases ◽  
Pulmonary Arteries ◽  
Mast Cell Activation ◽  
Tissue Destruction ◽  
Hypoxic Pulmonary Hypertension

Hypoxic pulmonary hypertension (HPH) is a syndrome characterized by the increase of pulmonary vascular tone and the structural remodeling of peripheral pulmonary arteries. Mast cells have an important role in many inflammatory diseases and they are also involved in tissue remodeling. Tissue hypoxia is associated with mast cell activation and the release of proteolytic enzymes, angiogenic and growth factors which mediate tissue destruction and remodeling in a variety of physiological and pathological conditions. Here we focused on the role of mast cells in the pathogenesis of hypoxic pulmonary hypertension from the past to the present.

scholarly journals The Role of Collagen Synthesis in Ventricular and Vascular Adaptation to Hypoxic Pulmonary Hypertension

2013 ◽  
Vol 135 (2) ◽  
Author(s):  
David Schreier ◽  
Timothy Hacker ◽  
Gouqing Song ◽  
Naomi Chesler
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Collagen Synthesis ◽  
Chronic Hypoxia ◽  
Coupling Efficiency ◽  
Pulmonary Arteries ◽  
Collagen Accumulation ◽  
The Impact ◽  
Rv Function

Pulmonary arterial hypertension (PAH) is a rapidly fatal disease in which mortality is typically due to right ventricular (RV) failure. An excellent predictor of mortality in PAH is proximal pulmonary artery stiffening, which is mediated by collagen accumulation in hypoxia-induced pulmonary hypertension (HPH) in mice. We sought to investigate the impact of limiting vascular and ventricular collagen accumulation on RV function and the hemodynamic coupling efficiency between the RV and pulmonary vasculature. Inbred mice were exposed to chronic hypoxia for 10 days with either no treatment (HPH) or with treatment with a proline analog that impairs collagen synthesis (CHOP-PEG; HPH + CP). Both groups were compared to control mice (CTL) exposed only to normoxia (no treatment). An admittance catheter was used to measure pressure-volume loops at baseline and during vena cava occlusion, with mice ventilated with either room air or 8% oxygen, from which pulmonary hemodynamics, RV function, and ventricular-vascular coupling efficiency (ηvvc) were calculated. Proline analog treatment limited increases in RV afterload (neither effective arterial elastance Ea nor total pulmonary vascular resistance significantly increased compared to CTL with CHOP-PEG), limited the development of pulmonary hypertension (CHOP-PEG reduced right ventricular systolic pressure by 10% compared to HPH, p < 0.05), and limited RV hypertrophy (CHOP-PEG reduced RV mass by 18% compared to HPH, p < 0.005). In an acutely hypoxic state, treatment improved RV function (CHOP-PEG increased end-systolic elastance Ees by 43%, p < 0.05) and maintained ηvvc at control, room air levels. CHOP-PEG also decreased lung collagen content by 12% measured biochemically compared to HPH (p < 0.01), with differences evident in large and small pulmonary arteries by histology. Our results demonstrate that preventing new collagen synthesis limits pulmonary hypertension development by reducing collagen accumulation in the pulmonary arteries that affect RV afterload. In particular, the proline analog limited structural and functional changes in distal pulmonary arteries in this model of early and somewhat mild pulmonary hypertension. We conclude that collagen plays an important role in small pulmonary artery remodeling and, thereby, affects RV structure and function changes induced by chronic hypoxia.

Role of Collagen Content and Cross-Linking in Large Pulmonary Arterial Stiffening During Hypoxic Pulmonary Hypertension

2010 ◽  
Author(s):  
Zhijie Wang ◽  
Naomi C. Chesler
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Morphological Changes ◽  
Strong Predictor ◽  
Collagen Content ◽  
Cross Linking ◽  
Hypoxic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
The Right

Chronic hypoxic pulmonary hypertension (HPH) is associated with large, conduit pulmonary arterial (PA) remodeling, which is characterized by morphological changes such as accumulation of collagen and elastin and wall thickening1–4. It is estimated that large PA stiffening accounts for over a third of the right ventricular workload increase in pulmonary arterial hypertension5. In this disease state, conduit PA stiffness is a strong predictor of mortality6, 7.

The distribution of the obstruction in the pulmonary arteries modifies pulsatile right ventricular afterload in pulmonary hypertension

2015 ◽  
Vol 181 ◽  
pp. 232-234 ◽  
Author(s):  
Maria J. Ruiz-Cano ◽  
J.C. Grignola ◽  
Joan A. Barberá ◽  
S. Garcia Garcia ◽  
M. Lázaro Salvador ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Pulmonary Arteries ◽  
Right Ventricular Afterload ◽  
Ventricular Afterload

scholarly journals Increased TMEM16A-encoded calcium-activated chloride channel activity is associated with pulmonary hypertension

2012 ◽  
Vol 303 (12) ◽  
pp. C1229-C1243 ◽  
Author(s):  
Abigail S. Forrest ◽  
Talia C. Joyce ◽  
Marissa L. Huebner ◽  
Ramon J. Ayon ◽  
Michael Wiwchar ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Electromechanical Coupling ◽  
Pulmonary Arteries ◽  
Doppler Imaging ◽  
Heart Weight ◽  
Channel Activity ◽  
Cl Channels ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

Pulmonary artery smooth muscle cells (PASMCs) are more depolarized and display higher Ca2+ levels in pulmonary hypertension (PH). Whether the functional properties and expression of Ca2+-activated Cl− channels (ClCa), an important excitatory mechanism in PASMCs, are altered in PH is unknown. The potential role of ClCa channels in PH was investigated using the monocrotaline (MCT)-induced PH model in the rat. Three weeks postinjection with a single dose of MCT (50 mg/kg ip), the animals developed right ventricular hypertrophy (heart weight measurements) and changes in pulmonary arterial flow (pulse-waved Doppler imaging) that were consistent with increased pulmonary arterial pressure and PH. Whole cell patch experiments revealed an increase in niflumic acid (NFA)-sensitive Ca2+-activated Cl− current [ ICl(Ca)] density in PASMCs from large conduit and small intralobar pulmonary arteries of MCT-treated rats vs. aged-matched saline-injected controls. Quantitative RT-PCR and Western blot analysis revealed that the alterations in ICl(Ca) were accompanied by parallel changes in the expression of TMEM16A, a gene recently shown to encode for ClCa channels. The contraction to serotonin of conduit and intralobar pulmonary arteries from MCT-treated rats exhibited greater sensitivity to nifedipine (1 μM), an l-type Ca2+ channel blocker, and NFA (30 or 100 μM, with or without 10 μM indomethacin to inhibit cyclooxygenases) or T16AInh-A01 (10 μM), TMEM16A/ClCa channel inhibitors, than that of control animals. In conclusion, augmented ClCa/TMEM16A channel activity is a major contributor to the changes in electromechanical coupling of PA in this model of PH. TMEM16A-encoded channels may therefore represent a novel therapeutic target in this disease.

Sign in / Sign up

Export Citation Format

Share Document