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

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Abstract

Background: Arterial stiffening or reduced compliance of proximal pulmonary vessels has been shown to be an important predictor of outcomes in patients with pulmonary hypertension. Though current evidence indicates that arterial stiffening modulates flow pulsatility in downstream vessels and is likely related to microvascular damage in organs without extensive distributing arteries, the cellular mechanisms underlying this relationship in the pulmonary circulation are unexplored. Thus, this study was designed to examine the responses of the microvascular pulmonary endothelium to changes in flow pulsatility. Methods: A flow system was developed to reproduce arterial-like pulse flow waves with the capability of modulating flow pulsatility through regulation of upstream compliance. Pulmonary microvascular endothelial cells (PMVECs) were exposed to steady flow and pulse flow waves of varied pulsatility with varied hemodynamic energy (low: pulsatility index or PI = 1.0; medium: PI = 1.7; high: PI = 2.6) at flow frequency of 1 or 2 Hz for different durations (1 and 6 h). The mean flow rates in all the conditions were kept the same with shear stress at 14 dynes/cm2. Gene expression was evaluated by analyzing mRNA levels of adhesion molecules (ICAM-1, E-selectin), chemokine (MCP-1) and growth factor/receptor (VEGF, Flt-1) in PMVECs. Functional changes were observed with monocyte adhesion assay. Results: 1) Compared to either steady flow or low pulsatility flow, increased flow pulsatility for 1 h induced significant increases in mRNA levels of ICAM-1, E-selectin and MCP-1. 2) Sustained high pulsatility flow perfusion induced increases in ICAM, E-selectin, MCP-1, VEGF and its receptor Flt-1 expression. 3) Flow pulsatility effects on PMVECs were frequency-dependent with greater responses at 2 Hz and likely associated with the hemodynamic energy level. 4) Pulse flow waves with high flow pulsatility at 2 Hz induced leukocyte adhesion and recruitment to PMVECs. Conclusion: Increased upstream pulmonary arterial stiffness increases flow pulsatility in distal arteries and induces inflammatory gene expression, leukocyte adhesion and cell proliferation in the downstream PMVECs.

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Acknowledgments

This study was funded in part by grants from the Children’s Hospital at Denver (Research Scholar Development Award and CCTSI-K12 Award to W.T.) and the NIH (HL 067397, HL 072738, K24 HL051506 to R.S., HL-14985-36 and HL084923-03 to K.R.S.).

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Authors and Affiliations

  1. Department of Pediatrics–Cardiology, The Children’s Hospital, University of Colorado at Denver, Aurora, CO, 80045, USA

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

  2. Department of Mechanical Engineering, University of Colorado at Boulder, Boulder, CO, 80309, USA

    Robin Shandas & Wei Tan

  3. Center for Bioengineering, University of Colorado at Denver, Aurora, CO, 80045, USA

    Robin Shandas & Wei Tan

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  1. Min Li
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Correspondence to Wei Tan.

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Li, M., Scott, D.E., Shandas, R. et al. High Pulsatility Flow Induces Adhesion Molecule and Cytokine mRNA Expression in Distal Pulmonary Artery Endothelial Cells. Ann Biomed Eng 37, 1082–1092 (2009). https://doi.org/10.1007/s10439-009-9684-3

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