Reduction of vascular intimal-medial hyperplasia in polytetrafluoroethylene arteriovenous grafts via expression of an inhibitor of G protein signaling.
Polytetrafluoroethylene (PTFE) arteriovenous (AV) grafts are performed routinely for vascular access. The limited life span of PTFE grafts is a major cause of morbidity. Graft failure is attributed to venous outflow tract vascular smooth muscle (VSM) hyperplasia, which is linked to heterotrimeric G protein signaling. We proposed that expression of a peptide inhibitor of G(betagamma) signaling (betaARKct) in the venous outflow of PTFE grafts would reduce hyperplasia and prolong graft patency. Left carotid to right external jugular vein PTFE AV grafts were placed in swine. The isolated external jugular vein was treated with an adenovirus encoding betaARKct, empty adenovirus, or phosphate-buffered saline for approximately 25 min. After 7 or 28 days, flow probe analysis was performed and the vein was harvested and analyzed for cross-sectional area comparison. After both 7 and 28 days, when compared to controls, treated animals demonstrated a statistically significant reduction in VSM hyperplasia with a reduction in cross-sectional intimal and medial areas of >40% (p < 0.05). Flow was maintained in treated grafts, while control groups demonstrated a >50% reduction (p < 0.05) at 7 days. Further, treated grafts demonstrated significant improvement in graft patency at 28 days (100% vs. 12% for treated and untreated grafts, respectively). The inhibition of G(betagamma) signaling reduces intimal-medial hyperplasia and prolongs graft patency in PTFE AV grafts. This represents a novel molecular therapeutic strategy for improving the patency of vascular access grafts.
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Related Subject Headings
- beta-Adrenergic Receptor Kinases
- Tunica Media
- Tunica Intima
- Swine
- Signal Transduction
- Polytetrafluoroethylene
- Nerve Tissue Proteins
- Models, Animal
- Hyperplasia
- Genetic Therapy
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- beta-Adrenergic Receptor Kinases
- Tunica Media
- Tunica Intima
- Swine
- Signal Transduction
- Polytetrafluoroethylene
- Nerve Tissue Proteins
- Models, Animal
- Hyperplasia
- Genetic Therapy