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

Sanjay Misra, Alex A. Fu, Alessandra Puggioni, Kamran M. Karimi, Jayawant Mandrekar, James Glockner, Luis A. Juncos, Bilal Anwer, Antonio M. McGuire, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume294
Issue number5
DOIs
StatePublished - May 2008

Fingerprint

Matrix Metalloproteinase 1
Tissue Inhibitor of Metalloproteinase-1
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Vascular Endothelial Growth Factor A
Renal Dialysis
Pathologic Constriction
Vascular Endothelial Growth Factor Receptor
Up-Regulation
Transplants
Veins
Neointima
Tissue Inhibitor of Metalloproteinase-2
Magnetic Resonance Angiography
Chronic Renal Insufficiency
Smooth Muscle
Actins
Proteins
Swine

Keywords

  • Hemodialysis grafts
  • Matrix metalloproteinases
  • Tissue inhibitors of matrix metalloproteinase
  • Vascular biology
  • Vascular endothelial growth factor-A
  • Wall shear stress

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

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. / Misra, Sanjay; Fu, Alex A.; Puggioni, Alessandra; Karimi, Kamran M.; Mandrekar, Jayawant; Glockner, James; Juncos, Luis A.; Anwer, Bilal; McGuire, Antonio M.; Mukhopadhyay, Debabrata.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 294, No. 5, 05.2008.

Research output: Contribution to journalArticle

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AU - Karimi, Kamran M.

AU - Mandrekar, Jayawant

AU - Glockner, James

AU - Juncos, Luis A.

AU - Anwer, Bilal

AU - McGuire, Antonio M.

AU - Mukhopadhyay, Debabrata

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AB - 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.

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