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/cm(2). 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.
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/cm(2). 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.
Authors: X Peng; F A Recchia; B J Byrne; I S Wittstein; R C Ziegelstein; D A Kass Journal: Am J Physiol Cell Physiol Date: 2000-09 Impact factor: 4.249
Authors: Rob J Dekker; Simone van Soest; Ruud D Fontijn; Sonia Salamanca; Philip G de Groot; Ed VanBavel; Hans Pannekoek; Anton J G Horrevoets Journal: Blood Date: 2002-09-01 Impact factor: 22.113
Authors: Kendall S Hunter; Justin K Gross; Craig J Lanning; K Scott Kirby; Karrie L Dyer; D Dunbar Ivy; Robin Shandas Journal: Congenit Heart Dis Date: 2008 Mar-Apr Impact factor: 2.007
Authors: Michal Schäfer; Cynthia Myers; R Dale Brown; Maria G Frid; Wei Tan; Kendall Hunter; Kurt R Stenmark Journal: Curr Hypertens Rep Date: 2016-01 Impact factor: 5.369
Authors: Jing Tian; Sohrab Fratz; Yali Hou; Qing Lu; Agnes Görlach; John Hess; Christian Schreiber; Sanjeev A Datar; Peter Oishi; John Nechtman; Robert Podolsky; Jin-Xiong She; Jeffrey R Fineman; Stephen M Black Journal: Physiol Genomics Date: 2010-10-26 Impact factor: 3.107
Authors: R Blair Dodson; Paul J Rozance; Carson C Petrash; Kendall S Hunter; Virginia L Ferguson Journal: Am J Physiol Heart Circ Physiol Date: 2013-12-06 Impact factor: 4.733