High Pulsatility Flow Induces Adhesion Molecule and Cytokine mRNA Expression in Distal Pulmonary Artery Endothelial Cells

Li, Min; Scott, Devon; Shandas, Robin; Stenmark, Kurt R.; Tan, Wei

doi:10.1007/s10439-009-9684-3

Cited by 95 publications

(68 citation statements)

References 39 publications

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“…In our study, the mean flow rates in two flow conditions, high pulsatility flow (PI ϭ 1.7) and low pulsatility or steady flow (PI ϭ 0.2), were always the same and thus the average flow shear (12 dyn/cm 2 ) in the physiological range; the only difference is in the PI, which is modulated by a compliance-adjustment chamber. Our previous study demonstrated that the low pulsatility flows (PI Յ 1) were very different from high pulsatility flows in that they did not elicit endothelial dysfunction such as proinflammatory responses, or they even could protect ECs (23). Additionally, previous studies also showed that it was p-eNOS that was increased by high pulsatile flow compared with low pulsatile flow, whereas the total eNOS was found unchanged by high and low pulsatile flow conditions (56).…”

Section: Discussionmentioning

confidence: 91%

“…Regarding the design of PI condition in this study, previous studies showed that the mean flow PI in the large elastic PAs (i.e., the first two generations, main PA, left PA, and right PA) ranged from 4.4 to 5.1 in vivo, whereas the PI in the pulmonary capillaries decreased to ϳ1 in vivo (38,43). In addition, our previous study with flows of several PI conditions (1, 1.7, and 2.6) found that only flows with higher PI (1.7 and 2.6) exerted detrimental effects on endothelium when no elastic deformation existed (23). Thus, we have used a PI of 1.7 to represent a high pulsatility flow condition generated by "proximal" artery stiffening.…”

Section: Methodsmentioning

confidence: 90%

“…For all of the flow conditions, the same mean flow rate with a mean shear stress of 12 dyn/cm 2 was applied for 24 h. The mean flow shear used here is close to the mean resting flow shear stress measured in distal pulmonary artery in vivo (13 dyn/cm 2 ) (51). With a constant mean velocity and frequency, a flow condition with a higher PI denotes a higher energy level (23). Regarding the design of PI condition in this study, previous studies showed that the mean flow PI in the large elastic PAs (i.e., the first two generations, main PA, left PA, and right PA) ranged from 4.4 to 5.1 in vivo, whereas the PI in the pulmonary capillaries decreased to ϳ1 in vivo (38,43).…”

Section: Methodsmentioning

confidence: 99%

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High pulsatility flow stimulates smooth muscle cell hypertrophy and contractile protein expression

Scott

Yan

Shandas

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Proximal arterial stiffening is an important predictor of events in systemic and pulmonary hypertension, partly through its contribution to downstream vascular abnormalities. However, much remains undetermined regarding the mechanisms involved in the vascular changes induced by arterial stiffening. We therefore addressed the hypothesis that high pulsatility flow, caused by proximal arterial stiffening, induces downstream pulmonary artery endothelial cell (EC) dysfunction that in turn leads to phenotypic change of smooth muscle cells (SMCs). To test the hypothesis, we employed a model pulmonary circulation in which upstream compliance regulates the pulsatility of flow waves imposed onto a downstream vascular mimetic coculture composed of pulmonary ECs and SMCs. The effects of high pulsatility flow on SMCs were determined both in the presence and absence of ECs. In the presence of ECs, high pulsatility flow increased SMC size and expression of the contractile proteins, smooth muscle α-actin (SMA) and smooth muscle myosin heavy chain (SM-MHC), without affecting proliferation. In the absence of ECs, high pulsatility flow decreased SMC expression of SMA and SM-MHC, without affecting SMC size or proliferation. To identify the molecular signals involved in the EC-mediated SMC responses, mRNA and/or protein expression of vasoconstrictors [angiotensin-converting enzyme (ACE) and endothelin (ET)-1], vasodilator (eNOS), and growth factor (TGF-β1) in EC were examined. Results showed high pulsatility flow decreased eNOS and increased ACE, ET-1, and TGF-β1 expression. ACE inhibition with ramiprilat, ET-1 receptor inhibition with bosentan, and treatment with the vasodilator bradykinin prevented flow-induced, EC-dependent SMC changes. In conclusion, high pulsatility flow stimulated SMC hypertrophy and contractile protein expression by altering EC production of vasoactive mediators and cytokines, supporting the idea of a coupling between proximal vascular stiffening, flow pulsatility, and downstream vascular function.

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Section: Discussionmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

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High pulsatility flow stimulates smooth muscle cell hypertrophy and contractile protein expression

Scott

Yan

Shandas

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Several studies compared the impact of steady laminar shear and "realistic" arterial (pulsatile) waveforms on endothelial metabolism and report an increased expression of proinflammatory, proapoptotic, and procoagulant transcripts (25,26) and a reduction of eNOS expression under pulsatile waveforms (27). Himburg et al (28) examined the frequencydependent response of aortic endothelial cells to pulsatile shear stress.…”

Section: Pathophysiology Of Elevated Heart Ratementioning

confidence: 98%

Vascular Pathophysiology in Response to Increased Heart Rate

Custodis

Schirmer

Baumhäkel

et al. 2010

Journal of the American College of Cardiology

221

156

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This review summarizes the current literature and the open questions regarding the physiology and pathophysiology of the mechanical effects of heart rate on the vessel wall and the associated molecular signaling that may have implications for patient care. Epidemiological evidence shows that resting heart rate is associated with cardiovascular morbidity and mortality in the general population and in patients with cardiovascular disease. As a consequence, increased resting heart rate has emerged as an independent risk factor both in primary prevention and in patients with hypertension, coronary artery disease, and myocardial infarction. Experimental and clinical data suggest that sustained elevation of heart rate-independent of the underlying trigger-contributes to the pathogenesis of vascular disease. In animal studies, accelerated heart rate is associated with cellular signaling events leading to vascular oxidative stress, endothelial dysfunction, and acceleration of atherogenesis. The underlying mechanisms are only partially understood and appear to involve alterations of mechanic properties such as reduction of vascular compliance. Clinical studies reported a positive correlation between increased resting heart rate and circulating markers of inflammation. In patients with coronary heart disease, increased resting heart rate may influence the clinical course of atherosclerotic disease by facilitation of plaque disruption and progression of coronary atherosclerosis. While a benefit of pharmacological or interventional heart rate reduction on different vascular outcomes was observed in experimental studies, prospective clinical data are limited, and prospective evidence determining whether modulation of heart rate can reduce cardiovascular events in different patient populations is needed.

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“…This is beginning to change. Recent clinical work has highlighted the importance of PVS in the progression of PH (55, 84, 110), mechanical studies have begun to elucidate the gross vascular changes responsible for stiffening, and existing and novel studies of cellular mechanotransduction suggest PVS may play a role in pulmonary disease pathogenesis (104,105). Many of these concepts have been well-adopted by investigators studying the systemic vascular circuit in health and disease.…”

Section: Introductionmentioning

confidence: 99%

Pulmonary Vascular Stiffness: Measurement, Modeling, and Implications in Normal and Hypertensive Pulmonary Circulations

Hunter

Lammers

Shandas

2011

Comprehensive Physiology

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This article introduces the concept of pulmonary vascular stiffness, discusses its increasingly recognized importance as a diagnostic marker in the evaluation of pulmonary vascular disease, and describes methods to measure and model it clinically, experimentally, and computationally. It begins with a description of systems-level methods to evaluate pulmonary vascular compliance and recent clinical efforts in applying such techniques to better predict patient outcomes in pulmonary arterial hypertension. It then progresses from the systems-level to the local level, discusses proposed methods by which upstream pulmonary vessels increase in stiffness, introduces concepts around vascular mechanics, and concludes by describing recent work incorporating advanced numerical methods to more thoroughly evaluate changes in local mechanical properties of pulmonary arteries.

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High Pulsatility Flow Induces Adhesion Molecule and Cytokine mRNA Expression in Distal Pulmonary Artery Endothelial Cells

Cited by 95 publications

References 39 publications

High pulsatility flow stimulates smooth muscle cell hypertrophy and contractile protein expression

High pulsatility flow stimulates smooth muscle cell hypertrophy and contractile protein expression

Vascular Pathophysiology in Response to Increased Heart Rate

Pulmonary Vascular Stiffness: Measurement, Modeling, and Implications in Normal and Hypertensive Pulmonary Circulations

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