Early Effects of Arterial Hemodynamic Conditions on Human Saphenous Veins Perfused Ex Vivo

Mavromatis, Kreton; Fukai, Tohru; Tate, Matthew C.; Chesler, Naomi C.; Ku, David N.; Galis, Zorina S.

doi:10.1161/01.atv.20.8.1889

Cited by 51 publications

(53 citation statements)

References 45 publications

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“…Others have shown that a one-time stretch of human saphenous veins before culture can cause a significant increase in MMP-2 and MMP-9 activity after 7 days of ex vivo perfusion, demonstrating how even a short mechanical stimulus can cause prolonged MMP expression long after the stimulus is removed. 31,36 Similar to the findings presented in this report, Meng et al also showed that levels of proMMP-9, proMMP-2, and MMP-2 all were elevated by day 7 in both control and stretched vein segments, yet stretched veins still showed a significantly greater increase in MMP expression. 31 In addition, Meng et al also reported the inability to detect active MMP-9 in zymograms, hypothesizing that this was possibly due to quick release from or degradation within the tissue.…”

supporting

confidence: 88%

Hemodynamics and Axial Strain Additively Increase Matrix Remodeling and MMP-9, But Not MMP-2, Expression in Arteries Engineered by Directed Remodeling

Nichol

Khan

Birbach

et al. 2009

Tissue Engineering Part A

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We previously demonstrated the ability to create engineered arteries by carefully controlling the mechanical environment of intact arteries perfused ex vivo, yielding engineered arteries with native appearance and vasoactive response. Increased axial strain was sufficient to increase length up to 20% in 9 days through a growth and remodeling response. The amount of the achievable length increase, however, was highly dependent on the hemodynamic conditions acting through unknown mechanisms. Because matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) activity is increased, and often required, in mechanically induced remodeling in vivo, MMP-2 and MMP-9 expression was investigated to elucidate the hemodynamic mediation of artery length. Carotid arteries from 30 kg pigs were perfused for 9 days ex vivo at either in situ axial strain or with a gradual 50% increase in axial strain, under either arterial or reduced hemodynamics (*10% of arterial hemodynamics). MMP-2 protein expression increased roughly twofold, while MMP-9 expression increased threefold under either reduced hemodynamics or increased axial strain ( p < 0.05). The combination of reduced hemodynamics with increased axial strain demonstrated an additive increase in MMP-9 protein ( p < 0.05) with no further change in MMP-2 expression. To investigate the mechanism by which axial strain and hemodynamics could additively increase MMP-9 expression, the expression of nuclear factor kappa B (NF-kB) subunits p50 and p65 was evaluated. Axial strain stimulated p65 expression and localization, while hemodynamics increased p50 expression, with both molecules being expressed only when both mechanical stimuli were applied. These data suggest that MMP-9 expression can be simultaneously stimulated by separate mechanical stimuli mediated by p50 and p65 expression, and that by using conditions that maximize MMP-9 expression, we can create an optimal remodeling environment to better direct the growth of engineered arteries and other tissues.

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supporting

confidence: 88%

Hemodynamics and Axial Strain Additively Increase Matrix Remodeling and MMP-9, But Not MMP-2, Expression in Arteries Engineered by Directed Remodeling

Nichol

Khan

Birbach

et al. 2009

Tissue Engineering Part A

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“…1,2 Successful vein graft adaptation is a complex process that includes cell proliferation and migration, programmed cell death, and changes in production and degradation of the extracellular matrix as well as coordinating growth factors, producing a thicker walled vessel. [3][4][5][6][7] Some of the signal transduction pathways that are rapidly stimulated in the venous endothelium on exposure to the increased magnitude of pressure and shear stress in the arterial environment include activation of the mitogen-activated protein kinase, 8 the phosphatidyl-inositol-3-kinase-Akt, 9,10 and the vascular endothelial growth factor (VEGF) pathways. 11,12 We have previously demonstrated that VEGF stimulates endothelial proliferation, migration, and actin reorganization by the Akt-nitric oxide pathway, 13 and others have shown that VEGF inhibits vein graft intimal thickening in rabbits.…”

mentioning

confidence: 99%

Venous Identity Is Lost but Arterial Identity Is Not Gained During Vein Graft Adaptation

Kudo

Muto

Maloney

et al. 2007

ATVB

110

116

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Objectives— Ephrin ligands and Eph receptors are signaling molecules that are differentially expressed on arteries and veins during development. We examined whether Eph-B4, a venous marker, and Ephrin-B2, an arterial marker, are regulated during vein graft adaptation in humans and aged rats. Methods and Results— Eph-B4 transcripts and immunodetectable protein are downregulated in endothelial and smooth muscle cells of patent vein grafts in both humans and in aged rats, whereas Ephrin-B2 transcripts and protein are not strongly induced. Other markers of arterial identity, including dll4 and notch-4, are also not induced during vein graft adaptation in aged rats. Because VEGF-A is upstream of the Ephrin–Eph pathway, and expression of VEGF-A is induced only at early time points after exposure of the vein to the arterial environment, we inhibited VEGF-A in vein grafts using an siRNA-based approach. Vein grafts treated with siRNA directed against VEGF-A demonstrated a thicker intima-media containing α-actin, consistent with arterialization, but did not contain Eph-B4 or Ephrin-B2. Conclusions— Venous identity is preserved in the veins of aged animals, but is lost during adaptation to the arterial circulation; arterial markers are not induced. Markers of vessel identity are plastic in adults and their selective regulation may mediate vein graft adaptation to the arterial environment in aged animals and humans.

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“…Numerous studies have shown that MMPs and TIMPs play a significant role in the early stages of IH in response to altered hemodynamics and vascular injury [185][186][187]. For example, after 6 hours of ex vivo perfusion with arterial hemodynamics, expression of MMP-2 and MMP-9 was increased in human saphenous veins [142]. Other organ culture studies of human saphenous vein have shown increased production of MMP-9 and increased activation of MMP-2 [145,182,188] under arterial conditions.…”

Section: De-adhesion and Migrationmentioning

confidence: 99%

“…Once injury is perceived by a vein, the hyperplastic response is set into motion and can be [24,105,[132][133][134][135][136][137][138][139][140][141][142][143][144][145][146]. In order to inhibit the initiating events of AVG IH, it is probable that one must take into account each of these five processes.…”

Section: Hyperplasiamentioning

confidence: 99%

“…Other systems have been reported which were designed without the ability to accurately simulate the higher frequency content of the physiologic arterial pressure or flowrate waveforms. They instead were designed to generate certain desired static [256][257][258][259][260] or oscillatory [81,142,[261][262][263][264][265][266][267][268][269][270] signals for the purpose of estimating the biomechanical properties of blood vessel segments.…”

Section: The Concept Of Ex Vivo Perfusion Was Originally Investigatedmentioning

confidence: 99%

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In Situ Bioengineering of Arterial Vein Grafts

El-Kurdi

Morelli

Hong

et al. 2008

ASME 2008 Summer Bioengineering Conference, Parts a and B

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The autogenous saphenous vein remains the graft of choice for both coronary (500,000 annually in the US) and peripheral (80,000 annually) arterial bypass procedures. Failure of arterial vein grafts (AVGs) remains a major problem, and patients with failed grafts will die or require reoperation. Intimal hyperplasia (IH) accounts for 20% to 40% of all AVG failures. It is believed that this adverse pathological response by AVGs is largely due to their abrupt exposure to the significantly elevated circumferential wall stress (CWS) associated with the arterial system. We believe that if an AVG is given an ample opportunity to adapt and remodel to the stresses of its new environment, cellular injury may be reduced, thus limiting the initiating mechanisms of IH.The goal of this work was to develop a new mechanical conditioning paradigm, in the form of a peri-adventitially placed, biodegradable polymer wrap, to safely and functionally "arterialize" AVGs in situ. The polymer wrap was tuned so that as it degraded over a desired period of time, the mechanical support offered by it was reduced and the vein was exposed to gradually increasing levels of CWS in situ.To investigate the effects of mechanical conditioning on AVGs, we utilized both our well established, validated ex vivo vascular perfusion system (EVPS) as well as an appropriate preclinical animal model. The "engineering" component of this bioengineering study was to enhance our EVPS capabilities. Enhancements were made in the form of rigorous mathematical modeling, via subspace system identification, and automatic feedback control, via proportional iv integral and derivative control, of the arterial CWS and shear stress waveform generation capabilities of the EVPS. Pairs of freshly harvested porcine internal jugular veins (PIJVs) were perfused ex vivo under several biomechanical conditions. The acute hyperplastic response of PIJVs abruptly exposed to arterial hemodynamic conditions was compared to PIJVs perfused under normal venous conditions. In an attempt to attenuate this acute hyperplastic response, an ex vivo mechanical conditioning paradigm was imposed onto the PIJVs both via manual adjustment of EVPS parameters and via an adventitially placed tuned electrospun biodegradable polymer wrap. Early markers of IH were evaluated post-perfusion, and they included vascular smooth muscle cell apoptosis, proliferation, and phenotypic modulation. Quantification of these markers via immunohistochemical techniques provided the foundation for the final stage of this work. To assess the efficacy of the tuned electrospun biodegradable polymer wrap in attenuating the development of intimal hyperplasia in AVGs, a series of preclinical studies was performed in a pig model. PIJVs abruptly exposed to arterial levels of CWS showed a significant increase in apoptosis and in the number of synthetic smooth muscle cells, as well as a decrease in proliferation. Mechanical conditioning, via both manual adjustment of the EVPS parameters and placement of the biodegradable adventitial wra...

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Early Effects of Arterial Hemodynamic Conditions on Human Saphenous Veins Perfused Ex Vivo

Cited by 51 publications

References 45 publications

Hemodynamics and Axial Strain Additively Increase Matrix Remodeling and MMP-9, But Not MMP-2, Expression in Arteries Engineered by Directed Remodeling

Hemodynamics and Axial Strain Additively Increase Matrix Remodeling and MMP-9, But Not MMP-2, Expression in Arteries Engineered by Directed Remodeling

Venous Identity Is Lost but Arterial Identity Is Not Gained During Vein Graft Adaptation

In Situ Bioengineering of Arterial Vein Grafts

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