Acute Response of Human Aortic Endothelial Cells to Loss of Pulsatility as Seen during Cardiopulmonary Bypass

Abstract

Cardiopulmonary bypass (CPB) results in short-term (3–5 h) exposure to flow with diminished pulsatility often referred to as “continuous flow”. It is unclear if short-term exposure to continuous flow influences endothelial function, particularly, changes in levels of pro-inflammatory and pro-angiogenic cytokines. In this study, we used the endothelial cell culture model (ECCM) to evaluate if short-term (≤5 h) reduction in pulsatility alters levels of pro-inflammatory/pro-angiogenic cytokine levels. Human aortic endothelial cells (HAECs) cultured within the ECCM provide a simple model to evaluate endothelial cell function in the absence of confounding factors. HAECs were maintained under normal pulsatile flow for 24 h and then subjected to continuous flow (diminished pulsatile pressure and flow) as observed during CPB for 5 h. The ECCM replicated pulsatility and flow morphologies associated with normal hemodynamic status and CPB as seen with clinically used roller pumps. Levels of angiopoietin-2 (ANG-2), vascular endothelial growth factor-A (VEGF-A), and hepatocyte growth factor were lower in the continuous flow group in comparison to the pulsatile flow group whereas the levels of endothelin-1 (ET-1), granulocyte colony stimulating factor, interleukin-8 (IL-8) and placental growth factor were higher in the continuous flow group in comparison to the pulsatile flow group. Immunolabelling of HAECs subjected to continuous flow showed a decrease in expression of ANG-2 and VEGF-A surface receptors, tyrosine protein kinase-2 and Fms-related receptor tyrosine kinase-1, respectively. Given that the 5 h exposure to continuous flow is insufficient for transcriptional regulation, it is likely that pro-inflammatory/pro-angiogenic signaling observed was due to signaling molecules stored in Weible-Palade bodies (ET-1, IL-8, ANG-2) and via HAEC binding/uptake of soluble factors in media. These results suggest that even short-term exposure to continuous flow can potentially activate pro-inflammatory/pro-angiogenic signaling in cultured HAECs and pulsatile flow may be a successful strategy in reducing the undesirable sequalae following continuous flow CPB.

Tissue Chips and Microphysiological Systems for Disease Modeling and Drug Testing

“…In 2019, Haglund and others from our group also demonstrated that synchronous and asynchronous flow profiles similar to those of popular CF-VAD models could be replicated, with the synchronous flow requiring some alteration of the compliance element, and the asynchronous flow necessitating the addition of a second pulsatile pump [84]. In a recently accepted but not yet published study of ours, physiologic arterial flow parameters of 120/80 mmHg pressure, 6-10% EC strain, 15 dynes/cm 2 average shear stress, and 10-12 mL/min flow rate at 60-80 beats/min was achieved [85]. They also demonstrated CF-VAD-like parameters of 100 mmHg pressure (pulse pressure completely eliminated) and 12 mL/min flow rate within the same system.…”

Circulating miRNAs and Vascular Injury Markers Associate with Cardiovascular Function in Older Patients Reaching End-Stage Kidney Disease

“…The Windkessel effect of normal elastic arteries, such as the aorta, decreases the pulsatility of the blood pump out of the heart, converts it into a more constant outflow and thereby prevents damage to the microvasculature [ 21 ]. As this effect is compromised in patients with a PWV > 10 m/s, their microvasculature has to cope with a higher pulsatility, which could initiate the local endothelial cells to start producing more Ang-2 [ 43 , 44 ]. Indeed, Ang-2 was experimentally demonstrated to be involved in arterial stiffness [ 45 ].…”

Bicuspidalization of the Native Tricuspid Aortic Valve: A Porcine in Vivo Model of Bicuspid Aortopathy

“…24) Using an ex vivo experimental model of CPB, Nguyen et al showed that short-term exposure (≤5 h) to continuous non-pulsatile flow (vs. pulsatile flow) activated pro-inflammatory/pro-angiogenic signaling in cultured human aortic endothelial cells. 25) Understanding endothelial cell recovery after damage induced by extracorporeal circulation is important to understand the effects of hemodynamic stress after bicuspidalization.…”