title: Reduction of vascular intimal-medial hyperplasia in polytetrafluoroethylene arteriovenous grafts via expression of an inhibitor of G protein signaling.
abstract: 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.
authors.affiliation: Department of Surgery, Duke University Medical Center, DUMC Box 2622, Room 481 MSRB, Research Drive, Durham, NC, 27710, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Fields
authors.forename: Kamran
authors.initials: K
authors.lastname: Baig
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Gaca
authors.forename: Luther G
authors.initials: LG
authors.lastname: Milton
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Lawson
mesh_terms: D019412:Anatomy, Cross-Sectional; D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D001672:Biocompatible Materials / Q000009:adverse effects; D001807:Blood Vessel Prosthesis / Q000009:adverse effects; D015316:Genetic Therapy; D006965:Hyperplasia; D023421:Models, Animal; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D011138:Polytetrafluoroethylene / Q000009:adverse effects; D015398:Signal Transduction; D013552:Swine; D017539:Tunica Intima / Q000473:pathology*; D017540:Tunica Media / Q000473:pathology*; D051552:beta-Adrenergic Receptor Kinases / Q000096:biosynthesis*
chemical_list: D001672:Biocompatible Materials; C029152:G-substrate; D009419:Nerve Tissue Proteins; D011138:Polytetrafluoroethylene; D051552:beta-Adrenergic Receptor Kinases