Microvessel Mechanobiology in Pulmonary Arterial Hypertension

Bloodworth, Nathaniel C.; West, James; Merryman, W. David

doi:10.1161/hypertensionaha.114.04652

Cited by 27 publications

(19 citation statements)

References 56 publications

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“…18 At the cellular and molecular levels, alterations in extracellular membrane contents, transmission of force between the vascular walls and intrinsic cellular stiffening because of cytoskeletal organization induce the proliferative remodeling of small pulmonary arteries. 10 Our study showed that arterial stiffness was significantly higher in smokers than in non-smokers, and we found a positive dose-response relationship between the amount of smoking and arterial stiffness in smokers without COPD. However, association between the amount of smoking and baPWV in smokers have been inconsistent in previous studies.…”

Section: Discussionsupporting

confidence: 56%

“…8 Pulmonary hypertension is an irreversible fatal complication in smokers with COPD. 9,38 The stiffness of the pulmonary artery plays an important role for vascular remodeling, right ventricular overload, and pulmonary hypertension, 10 and previous studies have proposed that pulmonary vascular alterations are not only a complication of emphysema but may also lead to emphysema in smokers. 11 The cross-sectional area (CSA) of small pulmonary vessels can be quantitatively measured using chest computed tomography (CT) and a previous study showed the pulmonary vessels to be associated with the extent of emphysema and with acute exacerbation of COPD.…”

Section: Introductionmentioning

confidence: 99%

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Adverse effect of smoking on cross‐sectional area of small pulmonary vessel and arterial stiffness in healthy smokers without COPD

Park

Shin

et al. 2019

Clinical Respiratory J

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Introduction Because it induces systemic inflammation, smoking is a risk factor of atherosclerosis and pulmonary hypertension. The brachial‐ankle pulse wave velocity (baPWV) and cross‐sectional area (CSA) of small pulmonary vessels can be useful markers to assess early changes of arterial stiffness and pulmonary vascular alteration in smokers. Objectives This study aimed to explore association between the CSA of small pulmonary vessel and arterial stiffness in healthy male smokers. Methods We enrolled 90 male non‐smokers and 90 male smokers (age: 51.5 ± 9.7 years and 52.1 ± 7.9 years, respectively). All subjects underwent chest computed tomography (CT), pulmonary function test and baPWV measurement. We evaluated the total CSAs less than 5 mm2 using ImageJ software and divided by the total lung area (%CSA<5). We compared the association between baPWV and %CSA<5 in two groups as well as correlations among the amount of smoking, baPWV and %CSA<5. Multiple linear regression analysis using %CSA<5 as the dependent variable was also performed. Results The mean baPWV and mean %CSA<5 were significantly different between the smokers and non‐smokers. The pack‐years was significantly correlated with %CSA<5 (r = −0.631, P < 0.001) and baPWV (r = 0.534, P < 0.001) in smokers. In multiple linear regression analysis, age, pack‐years, FEV1/FVC and baPWV were associated with %CSA<5, regardless of body mass index, blood pressure and heart rate. Conclusions There is a dose‐response relationship between cigarette smoking and the CSA of small pulmonary vessels and arterial stiffness, respectively. Arterial stiffness, age, pack‐years and mild airflow impairment are independent predictors of small pulmonary vascular destruction in smokers.

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Adverse effect of smoking on cross‐sectional area of small pulmonary vessel and arterial stiffness in healthy smokers without COPD

Park

Shin

et al. 2019

Clinical Respiratory J

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“…The stiffness distribution presented may be bimodal, possibly indicative a heterogeneous deposition of ECM components in the vessel wall. Increased vascular stiffness has been hypothesized to be the pathologic feature of human PAH central to etiology [ 35 , 36 ], and so this prevention has high prognostic significance for translation potential.…”

Section: Resultsmentioning

confidence: 99%

Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension

et al. 2016

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Serotonergic anorexigens are the primary pharmacologic risk factor associated with pulmonary arterial hypertension (PAH), and the resulting PAH is clinically indistinguishable from the heritable form of disease, associated with BMPR2 mutations. Both BMPR2 mutation and agonists to the serotonin receptor HTR2B have been shown to cause activation of SRC tyrosine kinase; conversely, antagonists to HTR2B inhibit SRC trafficking and downstream function. To test the hypothesis that a HTR2B antagonist can prevent BMRP2 mutation induced PAH by restricting aberrant SRC trafficking and downstream activity, we exposed BMPR2 mutant mice, which spontaneously develop PAH, to a HTR2B antagonist, SB204741, to block the SRC activation caused by BMPR2 mutation. SB204741 prevented the development of PAH in BMPR2 mutant mice, reduced recruitment of inflammatory cells to their lungs, and reduced muscularization of their blood vessels. By atomic force microscopy, we determined that BMPR2 mutant mice normally had a doubling of vessel stiffness, which was substantially normalized by HTR2B inhibition. SB204741 reduced SRC phosphorylation and downstream activity in BMPR2 mutant mice. Gene expression arrays indicate that the primary changes were in cytoskeletal and muscle contractility genes. These results were confirmed by gel contraction assays showing that HTR2B inhibition nearly normalizes the 400% increase in gel contraction normally seen in BMPR2 mutant smooth muscle cells. Heritable PAH results from increased SRC activation, cellular contraction, and vascular resistance, but antagonism of HTR2B prevents SRC phosphorylation, downstream activity, and PAH in BMPR2 mutant mice.

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“…Physiologically, there is strong evidence that arterial stiffening contributes significantly to RV afterload and RV failure. Standard measurements of RV afterload using PVR account for only the steady-flow component of RV work, however, arterial stiffness is the critical determinate of RV pulsatile afterload ( Tan W. et al, 2014 ; Bloodworth et al, 2015 ). In the pulmonary circulation, pulsatile afterload contributes approximately 23% to the workload of the RV, and has not been found to change through the course of disease ( Saouti et al, 2010a ).…”

Section: Clinical Impact Of Vascular Stiffening In Phmentioning

confidence: 99%

Mechanobiological Feedback in Pulmonary Vascular Disease

et al. 2018

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Vascular stiffening in the pulmonary arterial bed is increasingly recognized as an early disease marker and contributor to right ventricular workload in pulmonary hypertension. Changes in pulmonary artery stiffness throughout the pulmonary vascular tree lead to physiologic alterations in pressure and flow characteristics that may contribute to disease progression. These findings have led to a greater focus on the potential contributions of extracellular matrix remodeling and mechanical signaling to pulmonary hypertension pathogenesis. Several recent studies have demonstrated that the cellular response to vascular stiffness includes upregulation of signaling pathways that precipitate further vascular remodeling, a process known as mechanobiological feedback. The extracellular matrix modifiers, mechanosensors, and mechanotransducers responsible for this process have become increasingly well-recognized. In this review, we discuss the impact of vascular stiffening on pulmonary hypertension morbidity and mortality, evidence in favor of mechanobiological feedback in pulmonary hypertension pathogenesis, and the major contributors to mechanical signaling in the pulmonary vasculature.

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Microvessel Mechanobiology in Pulmonary Arterial Hypertension

Cited by 27 publications

References 56 publications

Adverse effect of smoking on cross‐sectional area of small pulmonary vessel and arterial stiffness in healthy smokers without COPD

Adverse effect of smoking on cross‐sectional area of small pulmonary vessel and arterial stiffness in healthy smokers without COPD

Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension

Mechanobiological Feedback in Pulmonary Vascular Disease

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