Increased shear stress with upregulation of VEGF-A and its receptors and MMP-2, MMP-9, and TIMP-1 in venous stenosis of hemodialysis grafts

Abstract

Venous injury and subsequent venous stenosis formation are responsible for hemodialysis graft failure. Our hypothesis is that these pathological changes are in part related to changes in wall shear stress (WSS) that results in the activation of matrix regulatory proteins causing subsequent venous stenosis formation. In the present study, we examined the serial changes in WSS, blood flow, and luminal vessel area that occur subsequent to the placement of a hemodialysis graft in a porcine model of chronic renal insufficiency. We then determined the corresponding histological, morphometric, and kinetic changes of several matrix regulatory proteins including VEGF-A, its receptors, matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, and TIMP-2. WSS was estimated by obtaining blood flow and luminal vessel area by performing phase-contrast MRI with magnetic resonance angiography in 21 animals at 1 day after graft placement and prior to death on day 3 ( n = 7), day 7 ( n = 7), and day 14 ( n = 7). At all time points, the mean WSS at the vein-to-graft anastomosis was significantly higher than that at the control vein ( P < 0.05). WSS had a bimodal distribution with peaks on days 1 and 7 followed by a significant reduction in WSS by day 14 ( P < 0.05 compared with day 7) and a decrease in luminal vessel area compared with control vessels. By day 3, there was a significant increase in VEGF-A and pro-MMP-9 followed by, on day 7, increased pro-MMP-2, active MMP-2, and VEGF receptor (VEGFR)-2 ( P < 0.05) and, by day 14, increased VEGFR-1 and TIMP-1 ( P < 0.05) at the vein-to-graft anastomosis compared with control vessels. Over time, the neointima thickened and was composed primarily of α-smooth muscle actin-positive cells with increased cellular proliferation. Our data suggest that hemodialysis graft placement leads to early increases in WSS, VEGF-A, and pro-MMP-9 followed by subsequent increases in pro-MMP-2, active MMP-2, VEGFR-1, VEGFR-2, and TIMP-1, which may contribute to the development of venous stenosis.

Laminar high shear stress up-regulates type IV collagen synthesis and down-regulates MMP-2 secretion in endothelium. A quantitative analysis

“…However, little is known about the relationship between hemodynamic force and MMP-2 secretion by ECs, although MMP expression under high shear stress increases in grafted whole vessels, including smooth muscle and inflammatory cells (Abbruzzese et al 1998;Korshunov and Berk 2003;Misra et al 2008). Our current study using gelatinase activity assay estimated by zymography and measurement of MMP-2/GFP fusion protein showed that MMP-2 protein was remarkably lower in a conditioned medium of ECs under high shear stress than under static control.…”

Hemodialysis Vascular Access Dysfunction

“…Experimental studies of AVGs have demonstrated a differential upregulation of MMP-2 at the graft-vein anastomosis, with early expression (9 days) in the adventitia and a later expression (19 days) within the intima, supporting the concept of cellular migration from the adventitia to the intima 86 . Furthermore, linkages between hemodynamic shear stress and the expression of oxidative stress markers and cytokines have also been described in a porcine model of AVG stenosis 87 . Clinical studies of stenotic and thrombotic AVGs and AVFs have also demonstrated an upregulation of MMPs 88 , and have documented the co-localization of oxidative stress markers with inflammatory cytokines such as transforming growth factor-beta (TGF-), and platelet-derived growth factor (PDGF), within the neointima of both stenotic AVGs and AVFs 60 .…”

“…Hemodynamic sheer stresses play a significant role in development of neointimal hyperplasia 87,112,206,207 . Therefore, altering the sheer stress pattern to prevent turbulent, lowflow, and low-sheer stresses could reduce the development of neointimal hyperplasia.…”

Fluid Dynamics of Ventricular Filling in the Embryonic Heart

“…More specifically, fluid shear stress is thought to trigger biochemical cascades within the endothelial cells of the developing heart that regulate chamber and valve morphogenesis [2,9,10]. Fluid shear is also known to increase transcription rates of several genes that are thought to also be involved in the regulation of cardiac morphogenesis, such as vascular endothelial growth factor [11,12] and endothelial transforming growth factor [13]. One study has found that fluid shear might also increase the conduction velocities of action potentials in the myocardial layer of the developing heart [14].…”