TY - JOUR
T1 - Local overexpression of C-type natriuretic peptide ameliorates vascular adaptation of porcine hemodialysis grafts
AU - Rotmans, Joris I.
AU - Verhagen, Hence J. M.
AU - Velema, Evelyn
AU - de kleijn, Dominique P. V.
AU - van den Heuvel, Mieke
AU - Kastelein, John J. P.
AU - Pasterkamp, Gerard
AU - Stroes, Erik S. G.
PY - 2004
Y1 - 2004
N2 - Background. Outflow obstruction at the outflow tract of arteriovenous grafts contributes significantly to the poor patency rates of dialysis grafts in vivo. We addressed the potential of local periadventitial gene therapy at the outflow tract for improving access patency in a validated porcine model of arteriovenous grafts using an adenoviral vector encoding murine C-type natriuretic peptide (Ad.CNP). Methods. Gene transfer efficiency and optimal virus concentration were determined using Ad.LacZ on porcine jugular veins in vivo (N = 2). Next, in 14 pigs. arteriovenous grafts were implanted bilaterally, between the carotid artery and the jugular vein. followed local venous transduction with Ad.CNP (right) and Ad.mock (left). Transduction efficiency of Ad.CNP was evaluated by reverse transcription-polyrnerase chain reaction (RT-PCR) and cyclic guanosine monophosphate (cGMP) measurements (N = 2). Fourteen days after gene transfer, arteriovenous grafts were excised for histologic analysis (N = 12). Results. Ad.LacZ transduction (1 x 10E10 1U) of porcine veins resulted in evident expression of beta-galactosidase, mainly in the adventitia. At termination. intima/media ratio was decreased by 37% in CNP-treated veins, predominantly due to medial thickening (Ad.CNP 3.1 +/- 0.6 min 2 vs. Ad.mock 1.70 +/- 0.3 mm(2); P <0.01) rather than decreased intimal hyperplasia (NS). Adventitial delivery of CNP resulted in increased external elastic lamina (EEL) (Ad.CNP 11.8 &PLUSMN; 1.4 nim vs. Ad.mock 9.4 &PLUSMN; 1.0 mm; P = 0.04) and luminal area (Ad.CNP 10.7 &PLUSMN; 1.4 min 2 vs. Ad.mock 8.8 &PLUSMN; 1.7 mm(2); P = 0.05) at the venous anastomosis. Conclusion. Overexpression of CNP enhances venous medial thickening and increases outward remodeling in the outflow tract of porcine arteriovenous grafts. These findings underscore the potential of local gene-therapeutic interventions in preventing luminal narrowing at the outflow tract of hemodialysis grafts
AB - Background. Outflow obstruction at the outflow tract of arteriovenous grafts contributes significantly to the poor patency rates of dialysis grafts in vivo. We addressed the potential of local periadventitial gene therapy at the outflow tract for improving access patency in a validated porcine model of arteriovenous grafts using an adenoviral vector encoding murine C-type natriuretic peptide (Ad.CNP). Methods. Gene transfer efficiency and optimal virus concentration were determined using Ad.LacZ on porcine jugular veins in vivo (N = 2). Next, in 14 pigs. arteriovenous grafts were implanted bilaterally, between the carotid artery and the jugular vein. followed local venous transduction with Ad.CNP (right) and Ad.mock (left). Transduction efficiency of Ad.CNP was evaluated by reverse transcription-polyrnerase chain reaction (RT-PCR) and cyclic guanosine monophosphate (cGMP) measurements (N = 2). Fourteen days after gene transfer, arteriovenous grafts were excised for histologic analysis (N = 12). Results. Ad.LacZ transduction (1 x 10E10 1U) of porcine veins resulted in evident expression of beta-galactosidase, mainly in the adventitia. At termination. intima/media ratio was decreased by 37% in CNP-treated veins, predominantly due to medial thickening (Ad.CNP 3.1 +/- 0.6 min 2 vs. Ad.mock 1.70 +/- 0.3 mm(2); P <0.01) rather than decreased intimal hyperplasia (NS). Adventitial delivery of CNP resulted in increased external elastic lamina (EEL) (Ad.CNP 11.8 &PLUSMN; 1.4 nim vs. Ad.mock 9.4 &PLUSMN; 1.0 mm; P = 0.04) and luminal area (Ad.CNP 10.7 &PLUSMN; 1.4 min 2 vs. Ad.mock 8.8 &PLUSMN; 1.7 mm(2); P = 0.05) at the venous anastomosis. Conclusion. Overexpression of CNP enhances venous medial thickening and increases outward remodeling in the outflow tract of porcine arteriovenous grafts. These findings underscore the potential of local gene-therapeutic interventions in preventing luminal narrowing at the outflow tract of hemodialysis grafts
U2 - https://doi.org/10.1111/j.1523-1755.2004.00598.x
DO - https://doi.org/10.1111/j.1523-1755.2004.00598.x
M3 - Article
C2 - 15086933
SN - 0085-2538
VL - 65
SP - 1897
EP - 1905
JO - Kidney International
JF - Kidney International
IS - 5
ER -