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.

scholarly journals CREB depletion in smooth muscle cells promotes medial thickening, adventitial fibrosis and elicits pulmonary hypertension

2020 ◽  
Vol 10 (2) ◽  
pp. 204589401989837 ◽  
Author(s):  
Chrystelle V. Garat ◽  
Susan M. Majka ◽  
Timothy M. Sullivan ◽  
Joseph T. Crossno ◽  
Jane E.B. Reusch ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Right Ventricular ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Systolic Pressure ◽  
Muscle Cells

Levels of the cAMP-responsive transcription factor, CREB, are reduced in medial smooth muscle cells in remodeled pulmonary arteries from hypertensive calves and rats with chronic hypoxia-induced pulmonary hypertension. Here, we show that chronic hypoxia fails to promote CREB depletion in pulmonary artery smooth muscle cells or elicit significant remodeling of the pulmonary arteries in mice, suggesting that sustained CREB expression prevents hypoxia-induced pulmonary artery remodeling. This hypothesis was tested by generating mice, in which CREB was ablated in smooth muscle cells. Loss of CREB in smooth muscle cells stimulated pulmonary artery thickening, right ventricular hypertrophy, profound adventitial collagen deposition, recruitment of myeloid cells to the adventitia, and elevated right ventricular systolic pressure without exposure to chronic hypoxia. Isolated murine CREB-null smooth muscle cells exhibited serum-independent proliferation and hypertrophy in vitro and medium conditioned by CREB-null smooth muscle cells stimulated proliferation and expression of extracellular matrix proteins by adventitial fibroblasts. We conclude that CREB governs the pathologic switch from homeostatic, quiescent smooth muscle cells to proliferative, synthetic cells that drive arterial remodeling contributing to the development or pulmonary hypertension.

scholarly journals Delineating the molecular and histological events that govern right ventricular recovery using a novel mouse model of pulmonary artery de-banding

2019 ◽  
Vol 116 (10) ◽  
pp. 1700-1709 ◽  
Author(s):  
Mario Boehm ◽  
Xuefei Tian ◽  
Yuqiang Mao ◽  
Kenzo Ichimura ◽  
Melanie J Dufva ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Mouse Model ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Exercise Capacity ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Sequence Of Events ◽  
Reverse Remodelling ◽  
Rv Function

Abstract Aims The temporal sequence of events underlying functional right ventricular (RV) recovery after improvement of pulmonary hypertension-associated pressure overload is unknown. We sought to establish a novel mouse model of gradual RV recovery from pressure overload and use it to delineate RV reverse-remodelling events. Methods and results Surgical pulmonary artery banding (PAB) around a 26-G needle induced RV dysfunction with increased RV pressures, reduced exercise capacity and caused liver congestion, hypertrophic, fibrotic, and vascular myocardial remodelling within 5 weeks of chronic RV pressure overload in mice. Gradual reduction of the afterload burden through PA band absorption (de-PAB)—after RV dysfunction and structural remodelling were established—initiated recovery of RV function (cardiac output and exercise capacity) along with rapid normalization in RV hypertrophy (RV/left ventricular + S and cardiomyocyte area) and RV pressures (right ventricular systolic pressure). RV fibrotic (collagen, elastic fibres, and vimentin+ fibroblasts) and vascular (capillary density) remodelling were equally reversible; however, reversal occurred at a later timepoint after de-PAB, when RV function was already completely restored. Microarray gene expression (ClariomS, Thermo Fisher Scientific, Waltham, MA, USA) along with gene ontology analyses in RV tissues revealed growth factors, immune modulators, and apoptosis mediators as major cellular components underlying functional RV recovery. Conclusion We established a novel gradual de-PAB mouse model and used it to demonstrate that established pulmonary hypertension-associated RV dysfunction is fully reversible. Mechanistically, we link functional RV improvement to hypertrophic normalization that precedes fibrotic and vascular reverse-remodelling events.

Sex Differences in Right Ventricular-Vascular Coupling and Pulmonary Artery Impedance in Response to Chronic Hypoxia and Recovery

2012 ◽  
Author(s):  
Aiping Liu ◽  
Lian Tian ◽  
Diana M. Tabima ◽  
Naomi C. Chesler
Keyword(s):  
Pulmonary Artery ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Pulmonary Artery Hypertension ◽  
Vascular Impedance ◽  
Female Predominance ◽  
Collagen Accumulation ◽  
Dominant Disease ◽  
Pulmonary Arterial

Pulmonary artery hypertension (PAH) is a female dominant disease (the female-to-male ratio is 4:1), characterized by small distal pulmonary arterial narrowing and large proximal arterial stiffening, which increase right ventricle (RV) afterload and ultimately lead to RV failure [1,2]. Our recent studies have shown that collagen accumulation induced by chronic hypoxia increases the stiffness of the large extralobar pulmonary arteries (PAs) [3], and affects pulmonary vascular impedance (PVZ) [4]. The role of collagen in the female predominance in developing PAH has not been explored to date.

The Influence of Pulmonary Hemodynamics on Right Ventricular Function in Pulmonary Hypertension

2013 ◽  
Author(s):  
Vitaly O. Kheyfets ◽  
Lourdes Rios ◽  
Triston Smith ◽  
Theodore Schroeder ◽  
Jeffrey Mueller ◽  
...  
Keyword(s):  
Fluid Dynamics ◽  
Pulmonary Hypertension ◽  
Shear Stress ◽  
Right Ventricular ◽  
Pulmonary Arteries ◽  
Pulmonary Hemodynamics ◽  
Arterial Hemodynamics ◽  
Computational Fluid Dynamics Cfd ◽  
Pulmonary Arterial ◽  
Rv Function

Pulmonary arterial hypertension (PAH) is a degenerative disease that can lead to substantial morphometric remodeling of the pulmonary arteries. Previous studies have revealed coupling relationships between right ventricular (RV) function and pulmonary arterial hemodynamics. The objective of this study was to utilize computational fluid dynamics (CFD) to estimate spatially averaged Wall Shear Stress (WSS) for patients with PH and explore correlations between hemodynamics metrics and RV function.

scholarly journals P957 Prognostic value of pulmonary artery elastic properties in patients with pulmonary hypertension - a comparison of Eisenmenger syndrome to other types of pulmonary hypertension

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
R Enache ◽  
D N Radu ◽  
R Badea ◽  
L Predescu ◽  
P Platon ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Cardiac Death ◽  
Global Longitudinal Strain ◽  
Heart Catheterization ◽  
Vasodilator Therapy ◽  
Eisenmenger’S Syndrome ◽  
The Impact ◽  
Rv Function

Abstract Patients with Eisenmenger’s syndrome (ES) have better survival than other patients with pulmonary arterial hypertension (PAH) probably due to the preservation of right ventricular (RV) function. As in PAH patients RV remodeling and function depend not only on pulmonary artery (PA) pressure but also on the intrinsic properties of PA wall, there is also a possible role of PA stiffness (PAS) as outcome predictor in this setting. Purpose. To study the prognostic role of PAS parameters assessed by 2D transthoracic echocardiography in patients with ES compared to other patients with pulmonary hypertension (PH) receiving specific vasodilator therapy. Methods. Sixty-eight PH patients were enrolled: 27 ES patients and 41 non-ES patients, including patients with other types of PAH (12 idiopathic PAH, 5 operated congenital heart disease, 10 connective tissue disease, 7 other forms of PAH) or chronic thromboembolic PH (7 patients) receiving oral vasodilator therapy. Clinical data, B-type natriuretic peptide (BNP), RV function and PAS parameters were assessed: pulmonary capacitance (PC), PC indexed to body surface area (PC/BSA), pulsatility, elastic modulus (EP), beta-index. PH patients were followed-up for 2.9 years (4 months-6.8 years). Results. Pulmonary vascular resistance (PVR) assessed by right heart catheterization was similar in both groups (11.9 ± 8.0 vs 11.0 ± 6.4 Wood units, p = 0.68). ES patients had lower BNP levels (lnBNP 3.63 ± 1.31 vs 5.31 ± 1.33, p &lt; 0.001) and better RV function than non-ES patients: RV-free wall S wave, RV-S (12.2 ± 2.3 vs 10.2 ± 2.0 cm/s, p &lt; 0.001), RV fractional area change, RV-FAC (40 ± 7 vs 32 ± 9%, p &lt; 0.001), RV global longitudinal strain (RV-GLS) on 3 segments (-20.2 ± 4.4 vs -14.8 ± 6.0%, p = 0.001) or 6 segments (-16.2 ± 4.2 vs -13.1 ± 4.9%, p = 0.011). In ES patients PAS parameters were less impaired than in non-ES group (PC 1.68 ± 0.86 vs 1.18 ± 0.66 ml/mmHg, p = 0.014; PC/BSA 1.05 ± 0.53 vs 0.68 ± 0.37 ml/mmHg m2, p = 0.003; pulsatility 18.8 ± 8.4 vs 13.8 ± 6.4%, p = 0.007, EP 390.7 ± 198.6 vs 578.8 ± 341.6 mmHg, p = 0.007; beta index 6.09 ± 2.85 vs 10.77 ± 6.21, p &lt; 0.001). During follow-up, 12 cardiac deaths occurred: 1 in ES group and 11 in non-ES group (p = 0.021). In non-ES group, predictors of cardiac death were parameters of RV function and PAS: BNP levels (lnBNP 6.20 ± 1.10 in deceased patients vs 4.97 ± 1.27 in survivors, p = 0.007), RV-S (9.1 ± 2.0 vs 10.6 ± 1.9 cm/s, p = 0.038), RV-FAC (25 ± 8 vs 35 ± 7%, p = 0.001), RV-GLS on 3 segments (-11.1 ± 4.4 vs -16.2 ± 6.0%, p = 0.015) or 6 segments (-9.0 ± 3.7 vs -14.6 ± 4.4%, p = 0.001), PC (0.86 ± 0.29 vs 1.32 ± 0.72 ml/mmHg, p = 0.01; PC/BSA (0.51 ± 0.17 vs 0.76 ± 0.41 ml/mmHg m,2 p = 0.013). Conclusion: Patients with ES have better RV function and less impaired PAS compared to patients with other types of PH and similar PVR. Moreover, besides RV function, PAS parameters emerged as predictors of cardiac death in non-ES patients that had worse prognosis than ES patients. The impact of these findings on clinical outcomes in ES patients remains to be further studied.

scholarly journals Regulation of soluble guanylyl cyclase-α1 expression in chronic hypoxia-induced pulmonary hypertension: role of NFATc3 and HuR

2009 ◽  
Vol 297 (3) ◽  
pp. L475-L486 ◽  
Author(s):  
Sergio de Frutos ◽  
Carlos H. Nitta ◽  
Elizabeth Caldwell ◽  
Jessica Friedman ◽  
Laura V. González Bosc
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Guanylyl Cyclase ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Soluble Guanylyl Cyclase ◽  
Muscle Cells ◽  
Pulmonary Artery Smooth Muscle

The nitric oxide/soluble guanylyl cyclase (sGC) signal transduction pathway plays an important role in smooth muscle relaxation and phenotypic regulation. However, the transcriptional regulation of sGC gene expression is largely unknown. It has been shown that sGC expression increases in pulmonary arteries from chronic hypoxia-induced pulmonary hypertensive animals. Since the transcription factor NFATc3 is required for the upregulation of the smooth muscle hypertrophic/differentiation marker α-actin in pulmonary artery smooth muscle cells from chronically hypoxic mice, we hypothesized that NFATc3 is required for the regulation of sGC-α1 expression during chronic hypoxia. Exposure to chronic hypoxia for 2 days induced a decrease in sGC-α1 expression in mouse pulmonary arteries. This reduction was independent of NFATc3 but mediated by nuclear accumulation of the mRNA-stabilizing protein human antigen R (HuR). Consistent with our hypothesis, chronic hypoxia (21 days) upregulated pulmonary artery sGC-α1 expression, bringing it back to the level of the normoxic controls. This response was prevented in NFATc3 knockout and cyclosporin (calcineurin/NFATc inhibitor)-treated mice. Furthermore, we identified effective binding sites for NFATc in the mouse sGC-α1 promoter. Activation of NFATc3 increased sGC-α1 promoter activity in human embryonic derived kidney cells, rat aortic-derived smooth muscle cells, and human pulmonary artery smooth muscle cells. Our results suggest that NFATc3 and HuR are important regulators of sGC-α1 expression in pulmonary vascular smooth muscle cells during chronic hypoxia-induced pulmonary hypertension.

scholarly journals Role of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension

2014 ◽  
Vol 306 (1) ◽  
pp. H41-H52 ◽  
Author(s):  
Carlos H. Nitta ◽  
David A. Osmond ◽  
Lindsay M. Herbert ◽  
Britta F. Beasley ◽  
Thomas C. Resta ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Systolic Pressure ◽  
Arterial Remodeling ◽  
Ventricular Systolic Pressure ◽  
Intracellular Ca

Chronic hypoxia (CH) associated with respiratory disease results in elevated pulmonary vascular intracellular Ca2+ concentration, which elicits enhanced vasoconstriction and promotes vascular arterial remodeling and thus has important implications in the development of pulmonary hypertension (PH). Store-operated Ca2+ entry (SOCE) contributes to this elevated intracellular Ca2+ concentration and has also been linked to acute hypoxic pulmonary vasoconstriction (HPV). Since our laboratory has recently demonstrated an important role for acid-sensing ion channel 1 (ASIC1) in mediating SOCE, we hypothesized that ASIC1 contributes to both HPV and the development of CH-induced PH. To test this hypothesis, we examined responses to acute hypoxia in isolated lungs and assessed the effects of CH on indexes of PH, arterial remodeling, and vasoconstrictor reactivity in wild-type (ASIC1+/+) and ASIC1 knockout (ASIC1−/−) mice. Restoration of ASIC1 expression in pulmonary arterial smooth muscle cells from ASIC1−/− mice rescued SOCE, confirming the requirement for ASIC1 in this response. HPV responses were blunted in lungs from ASIC1−/− mice. Both SOCE and receptor-mediated Ca2+ entry, along with agonist-dependent vasoconstrictor responses, were diminished in small pulmonary arteries from control ASIC−/− mice compared with ASIC+/+ mice. The effects of CH to augment receptor-mediated vasoconstrictor and SOCE responses in vessels from ASIC1+/+ mice were not observed after CH in ASIC1−/− mice. In addition, ASIC1−/− mice exhibited diminished right ventricular systolic pressure, right ventricular hypertrophy, and arterial remodeling in response to CH compared with ASIC1+/+ mice. Taken together, these data demonstrate an important role for ASIC1 in both HPV and the development of CH-induced PH.

scholarly journals Regional Right Ventricular Abnormalities Implicate Distinct Pathophysiological Conditions in Patients With Chronic Thromboembolic Pulmonary Hypertension

2020 ◽  
Vol 9 (21) ◽  
Author(s):  
Hidenori Moriyama ◽  
Takashi Kawakami ◽  
Masaharu Kataoka ◽  
Takahiro Hiraide ◽  
Mai Kimura ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Pulmonary Vascular Resistance ◽  
Pulmonary Artery Pressure ◽  
Vascular Resistance ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Area Change ◽  
Thromboembolic Pulmonary Hypertension ◽  
Rv Function

Background Right ventricular (RV) dysfunction is a prognostic factor for cardiovascular disease. However, its mechanism and pathophysiology remain unknown. We investigated RV function using RV‐specific 3‐dimensional (3D)‐speckle‐tracking echocardiography (STE) in patients with chronic thromboembolic pulmonary hypertension. We also assessed regional wall motion abnormalities in the RV and chronological changes during balloon pulmonary angioplasty (BPA). Methods and Results Twenty‐nine patients with chronic thromboembolic pulmonary hypertension who underwent BPA were enrolled and underwent right heart catheterization and echocardiography before, immediately after, and 6 months after BPA. Echocardiographic assessment of RV function included both 2‐dimensional‐STE and RV‐specific 3D‐STE. Before BPA, global area change ratio measured by 3D‐STE was significantly associated with invasively measured mean pulmonary artery pressure and pulmonary vascular resistance ( r =0.671 and r =0.700, respectively). Dividing the RV into the inlet, apex, and outlet, inlet area change ratio showed strong correlation with mean pulmonary artery pressure and pulmonary vascular resistance before BPA ( r =0.573 and r =0.666, respectively). Only outlet area change ratio was significantly correlated with troponin T values at 6 months after BPA ( r =0.470), and its improvement after BPA was delayed compared with the inlet and apex regions. Patients with poor outlet area change ratio were associated with a delay in RV reverse remodeling after treatment. Conclusions RV‐specific 3D‐STE analysis revealed that 3D RV parameters were novel useful indicators for assessing RV function and hemodynamics in pulmonary hypertension and that each regional RV portion presents a unique response to hemodynamic changes during treatment, implicating that evaluation of RV regional functions might lead to a new guide for treatment strategies.

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].

scholarly journals Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

2015 ◽  
Vol 308 (7) ◽  
pp. L719-L728 ◽  
Author(s):  
Raed Alhawaj ◽  
Dhara Patel ◽  
Melissa R. Kelly ◽  
Dong Sun ◽  
Michael S. Wolin
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Chronic Hypoxia ◽  
Aminolevulinic Acid ◽  
Pulmonary Arteries ◽  
Protoporphyrin Ix ◽  
Heme Biosynthesis ◽  
Mitochondrial Superoxide ◽  
Stat3 Phosphorylation ◽  
Biosynthesis Modulation

This study examines how heme biosynthesis modulation with δ-aminolevulinic acid (ALA) potentially functions to prevent 21-day hypoxia (10% oxygen)-induced pulmonary hypertension in mice and the effects of 24-h organoid culture with bovine pulmonary arteries (BPA) with the hypoxia and pulmonary hypertension mediator endothelin-1 (ET-1), with a focus on changes in superoxide and regulation of micro-RNA 204 (miR204) expression by src kinase phosphorylation of signal transducer and activator of transcription-3 (STAT3). The treatment of mice with ALA attenuated pulmonary hypertension (assessed through echo Doppler flow of the pulmonary valve, and direct measurements of right ventricular systolic pressure and right ventricular hypertrophy), increases in pulmonary arterial superoxide (detected by lucigenin), and decreases in lung miR204 and mitochondrial superoxide dismutase (SOD2) expression. ALA treatment of BPA attenuated ET-1-induced increases in mitochondrial superoxide (detected by MitoSox), STAT3 phosphorylation, and decreases in miR204 and SOD2 expression. Because ALA increases BPA protoporphyrin IX (a stimulator of guanylate cyclase) and cGMP-mediated protein kinase G (PKG) activity, the effects of the PKG activator 8-bromo-cGMP were examined and found to also attenuate the ET-1-induced increase in superoxide. ET-1 increased superoxide production and the detection of protoporphyrin IX fluorescence, suggesting oxidant conditions might impair heme biosynthesis by ferrochelatase. However, chronic hypoxia actually increased ferrochelatase activity in mouse pulmonary arteries. Thus, a reversal of factors increasing mitochondrial superoxide and oxidant effects that potentially influence remodeling signaling related to miR204 expression and perhaps iron availability needed for the biosynthesis of heme by the ferrochelatase reaction could be factors in the beneficial actions of ALA in pulmonary hypertension.

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