Pulmonary vascular remodeling in isolated mouse lungs: Effects on pulsatile pressure–flow relationships

Tuchscherer, Holly A.; Vanderpool, Rebecca; Chesler, Naomi C.

doi:10.1016/j.jbiomech.2006.03.023

Cited by 40 publications

(50 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The index of wave reflections (Γ) is the ratio of the difference between zero-frequency impedance (PVR) and the characteristic impedance and their sum. Characteristic impedance is known to stay relatively constant over the course of PH; 20,21 this is believed to be due to a synchronized increase in stiffness and fluid inertia. Therefore, an increase in PVR would cause the numerator in the equation for Γ to increase disproportionally, compared to the denominator, increasing Γ and suggesting an early return of the reflected waves due to an increase in pulmonary stiffness (and thus pulse wave velocity).…”

Section: Discussionmentioning

confidence: 99%

The Role of Wall Shear Stress in the Assessment of Right Ventricle Hydraulic Workload

et al. 2015

View full text Add to dashboard Cite

Pulmonary hypertension (PH) is a devastating disease affecting approximately 15-50 people per million, with a higher incidence in women. PH mortality is mostly attributed to right ventricle (RV) failure, which results from RV hypotrophy due to an overburdened hydraulic workload. The objective of this study is to correlate wall shear stress (WSS) with hemodynamic metrics that are generally accepted as clinical indicators of RV workload and are well correlated with disease outcome. Retrospective right heart catheterization data for 20 PH patients were analyzed to derive pulmonary vascular resistance (PVR), arterial compliance (C), and an index of wave reflections (Γ). Patient-specific contrast-enhanced computed tomography chest images were used to reconstruct the individual pulmonary arterial trees up to the seventh generation. Computational fluid dynamics analyses simulating blood flow at peak systole were conducted for each vascular model to calculate WSS distributions on the endothelial surface of the pulmonary arteries. WSS was found to be decreased proportionally with elevated PVR and reduced C. Spatially averaged WSS (SAWSS) was positively correlated with PVR (R 2 ¼ 0.66), C (R 2 ¼ 0.73), and Γ (R 2 ¼ 0.5) and also showed promising preliminary correlations with RV geometric characteristics. Evaluating WSS at random cross sections in the proximal vasculature (main, right, and left pulmonary arteries), the type of data that can be acquired from phase-contrast magnetic resonance imaging, did not reveal the same correlations. In conclusion, we found that WSS has the potential to be a viable and clinically useful noninvasive metric of PH disease progression and RV health. Future work should be focused on evaluating whether SAWSS has prognostic value in the management of PH and whether it can be used as a rapid reactivity assessment tool, which would aid in selection of appropriate therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

The Role of Wall Shear Stress in the Assessment of Right Ventricle Hydraulic Workload

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Interestingly, in the normoxic condition, the Col1a1 R/R mice had lower mean PA pressures than Col1a1 ϩ/ϩ mice and had a larger relative increase in mean PA pressure with exposure to hypoxia. In response to hypoxia, distal arteriolar muscularization and narrowing are largely responsible for increases in mean PA pressure and pulmonary vascular resistance (44). Collagen degradation is known to play an active role in this process; in particular, mRNA levels of MMP-8, which has substrate affinity for fibrillar collagens type I and III, increases rapidly and significantly in response to chronic hypoxia (6).…”

Section: Discussionmentioning

confidence: 99%

“…Conduit PA stiffening likely increases wave reflections to impair right ventricular systolic function, much like aortic stiffening impairs left ventricular systolic function (18,29,33). Our laboratory has previously shown that HPH increases wave reflections in the mouse pulmonary circulation (44). Recent evidence showing that conduit PA stiffness is a strong predictor of mortality in PA hypertension (12,30) further supports the importance of PA stiffness to pulmonary and right ventricular function.…”

mentioning

confidence: 88%

The role of collagen in extralobar pulmonary artery stiffening in response to hypoxia-induced pulmonary hypertension

Ooi¹,

Wang²,

Tabima³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

113

View full text Add to dashboard Cite

Chesler NC. The role of collagen in extralobar pulmonary artery stiffening in response to hypoxia-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 299: H1823-H1831, 2010. First published September 17, 2010 doi:10.1152/ajpheart.00493.2009.-Hypoxic pulmonary hypertension (HPH) causes extralobar pulmonary artery (PA) stiffening, which potentially impairs right ventricular systolic function. Changes in the extracellular matrix proteins collagen and elastin have been suggested to contribute to this arterial stiffening. We hypothesized that vascular collagen accumulation is a major cause of extralobar PA stiffening in HPH and tested our hypothesis with transgenic mice that synthesize collagen type I resistant to collagenase degradation (Col1a1 R/R ). These mice and littermate controls that have normal collagen degradation (Col1a1 ϩ/ϩ ) were exposed to hypoxia for 10 days; some were allowed to recover for 32 days. In vivo PA pressure and isolated PA mechanical properties and collagen and elastin content were measured for all groups. Vasoactive studies were also performed with U-46619, Y-27632, or calcium-and magnesium-free medium. Pulmonary hypertension occurred in both mouse strains due to chronic hypoxia and resolved with recovery. HPH caused significant PA mechanical changes in both mouse strains: circumferential stretch decreased, and mid-to-high-strain circumferential elastic modulus increased (P Ͻ 0.05 for both). Impaired collagen type I degradation prevented a return to baseline mechanical properties with recovery and, in fact, led to an increase in the low and mid-to-highstrain moduli compared with hypoxia (P Ͻ 0.05 for both). Significant changes in collagen content were found, which tended to follow changes in mid-to-high-strain elastic modulus. No significant changes in elastin content or vasoactivity were observed. Our results demonstrate that collagen content is important to extralobar PA stiffening caused by chronic hypoxia. biomechanics; mechanobiology; elastin; hydroxyproline; recovery HYPOXIC PULMONARY HYPERTENSION (HPH) is caused by living at high altitudes and is a complication of many lung diseases, including chronic obstructive pulmonary disease (1, 13, 16), cystic fibrosis (10), and obstructive sleep apnea (13), which contributes significantly to morbidity and mortality. Pulmonary vascular remodeling due to chronic HPH increases conduit pulmonary artery (PA) stiffness (4,20,21,23,34,42). Conduit PA stiffening likely increases wave reflections to impair right ventricular systolic function, much like aortic stiffening impairs left ventricular systolic function (18,29,33). Our laboratory has previously shown that HPH increases wave reflections in the mouse pulmonary circulation (44). Recent evidence showing that conduit PA stiffness is a strong predictor of mortality in PA hypertension (12, 30) further supports the importance of PA stiffness to pulmonary and right ventricular function.The dominant morphological changes in conduit PAs in response to HPH are accumulation of collagen and ...

show abstract

“…Only brief increases in SMC proliferation are noted, with some reports demonstrating an overall decrease in SMC numbers late in the exposure (127). In addition, thickening of proximal pulmonary arteries is observed with adventitial thickening and fibrosis and functional increases in the stiffening of these arteries (42,169). From a molecular point of view, definite differences between the response of the rat and mouse to hypoxia have also been shown.…”

Section: Classic Animal Models Of Phmentioning

confidence: 99%

Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure

Stenmark

Meyrick

Galiè

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

683

736

View full text Add to dashboard Cite

At present, six groups of chronic pulmonary hypertension (PH) are described. Among these, group 1 (and 1') comprises a group of diverse diseases termed pulmonary arterial hypertension (PAH) that have several pathophysiological, histological, and prognostic features in common. PAH is a particularly severe and progressive form of PH that frequently leads to right heart failure and premature death. The diagnosis of PAH must include a series of defined clinical parameters, which extend beyond mere elevations in pulmonary arterial pressures and include precapillary PH, pulmonary hypertensive arteriopathy (usually with plexiform lesions), slow clinical onset (months or years), and a chronic time course (years) characterized by progressive deterioration. What appears to distinguish PAH from other forms of PH is the severity of the arteriopathy observed, the defining characteristic of which is "plexogenic arteriopathy." The pathogenesis of this arteriopathy remains unclear despite intense investigation in a variety of animal model systems. The most commonly used animal models ("classic" models) are rodents exposed to either hypoxia or monocrotaline. Newer models, which involve modification of classic approaches, have been developed that exhibit more severe PH and vascular lesions, which include neointimal proliferation and occlusion of small vessels. In addition, genetically manipulated mice have been generated that have provided insight into the role of specific molecules in the pulmonary hypertensive process. Unfortunately, at present, there is no perfect preclinical model that completely recapitulates human PAH. All models, however, have provided and will continue to provide invaluable insight into the numerous pathways that contribute to the development and maintenance of PH. Use of both classic and newly developed animal models will allow continued rigorous testing of new hypotheses regarding pathogenesis and treatment. This review highlights progress that has been made in animal modeling of this important human condition.

show abstract

Pulmonary vascular remodeling in isolated mouse lungs: Effects on pulsatile pressure–flow relationships

Cited by 40 publications

References 35 publications

The Role of Wall Shear Stress in the Assessment of Right Ventricle Hydraulic Workload

The Role of Wall Shear Stress in the Assessment of Right Ventricle Hydraulic Workload

The role of collagen in extralobar pulmonary artery stiffening in response to hypoxia-induced pulmonary hypertension

Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure

Contact Info

Product

Resources

About