doi: 10.1161/hc3801.095693
(Circulation. 2001;104:1526.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Nitric Oxide Synthase (nNOS) Gene Transfer Modifies Venous Bypass Graft Remodeling
Effects on Vascular Smooth Muscle Cell Differentiation and Superoxide Production
From the Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (N.E.J.W., T.J.G., E.B., S.C., K.M.C.), and the Cardiovascular Division, Duke University Medical Center, Durham, NC (H.Q., S.E.G.).
Correspondence to Keith M. Channon, MD, MRCP, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail keith.channon{at}cardiov.ox.ac.uk
Background— Pathological vascular remodeling in venous bypass grafts (VGs) results in smooth muscle cell (SMC) intimal hyperplasia and provides the substrate for progressive atherosclerosis, the principal cause of late VG failure. Nitric oxide (NO) bioactivity is reduced in VGs, in association with increased vascular superoxide production, but how these features relate to pathological VG remodeling remains unclear. We used gene transfer of the neuronal isoform of nitric oxide synthase (nNOS) to investigate how increased NO production modulates vascular remodeling in VGs and determined the effects on late VG phenotype.
Methods and Results— New Zealand White rabbits (n=60) underwent jugular-carotid interposition bypass graft surgery with intraoperative adenoviral gene transfer of nNOS or ß-galactosidase. Vessels were analyzed after 3 days (early, to investigate acute injury/inflammation) or 28 days (late, to investigate SMC intimal hyperplasia). In early VGs, nNOS gene transfer significantly increased NOS activity and substantially reduced adhesion molecule expression and inflammatory cell infiltration. In late VGs, recombinant nNOS protein was no longer evident, but there were sustained effects on VG remodeling, resulting in a striking reduction in SMC intimal hyperplasia, a more differentiated intimal SMC phenotype, and reduced vascular superoxide production.
Conclusions— Intraoperative nNOS gene transfer has sustained favorable effects on VG remodeling and on the vascular phenotype of mature VGs. These findings suggest that early, transient modification of the response to vascular injury is a powerful approach to modulate VG biology and highlight the potential utility of NOS gene transfer as a therapeutic strategy in VGs.
Key Words: grafting • superoxide • nitric oxide • vasculature • muscle, smooth
This article has been cited by other articles:
 |
|
 |
|
  L. Wang, D. Li, T. A. Dawson, and D. J. Paterson Long-term effect of neuronal nitric oxide synthase over-expression on cardiac neurotransmission mediated by a lentiviral vector J. Physiol., July 15, 2009; 587(14): 3629 - 3637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. A. Ali, C. A. Bursill, G. Douglas, E. McNeill, M. Papaspyridonos, A. L. Tatham, J. K. Bendall, A. M. Akhtar, N. J. Alp, D. R. Greaves, et al. CCR2-Mediated Antiinflammatory Effects of Endothelial Tetrahydrobiopterin Inhibit Vascular Injury-Induced Accelerated Atherosclerosis Circulation, September 30, 2008; 118(14_suppl_1): S71 - S77. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kanno, T. Into, C. J. Lowenstein, and K. Matsushita Nitric oxide regulates vascular calcification by interfering with TGF-{beta} signalling Cardiovasc Res, January 1, 2008; 77(1): 221 - 230. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gaudino, N. Luciani, F. Glieca, C. Cellini, C. Pragliola, C. Trani, F. Burzotta, G. Schiavoni, A. Anselmi, and G. Possati Patients with in-stent restenosis have an increased risk of mid-term venous graft failure. Ann. Thorac. Surg., September 1, 2006; 82(3): 802 - 804. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Mayr, Y. Zou, Z. Zhang, H. Dietrich, Y. Hu, and Q. Xu Accelerated Arteriosclerosis of Vein Grafts in Inducible NO Synthase-/- Mice Is Related to Decreased Endothelial Progenitor Cell Repair Circ. Res., February 17, 2006; 98(3): 412 - 420. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. W.H. van der Heijden, Y. P.G. Essers, G. Fazzi, L. L.H. Peeters, J. G.R. De Mey, and G. J.J.M. van Eys Uterine Artery Remodeling and Reproductive Performance Are Impaired in Endothelial Nitric Oxide Synthase-Deficient Mice Biol Reprod, May 1, 2005; 72(5): 1161 - 1168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Chandiwal, V. Balasubramanian, Z. K. Baldwin, M. S. Conte, and L. B. Schwartz Gene Therapy for the Extension of Vein Graft Patency: A Review Vascular and Endovascular Surgery, January 1, 2005; 39(1): 1 - 14. [Abstract] [PDF]
|
|
|
|
 |
|
 A. C. Newby Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic Plaque Rupture Physiol Rev, January 1, 2005; 85(1): 1 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hattan, D. Warltier, W. Gu, C. Kolz, W. M. Chilian, and D. Weihrauch Autologous vascular smooth muscle cell-based myocardial gene therapy to induce coronary collateral growth Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H488 - H493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. von der Thusen, M. L. Fekkes, R. Passier, A.J. van Zonneveld, V. Mainfroid, T. J.C. van Berkel, and E. A.L. Biessen Adenoviral Transfer of Endothelial Nitric Oxide Synthase Attenuates Lesion Formation in a Novel Murine Model of Postangioplasty Restenosis Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 357 - 362. [Abstract] [Full Text]
|
|
|
|
|
|
N. J Alp, N. E.J West, N. Arnold, J. Gunn, A. P Banning, and K. M Channon Increased intimal hyperplasia in experimental vein graft stenting compared to arterial stenting: comparisons in a new rabbit model of stent injury Cardiovasc Res, October 1, 2002; 56(1): 164 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Guzik, N. E.J. West, R. Pillai, D. P. Taggart, and K. M. Channon Nitric Oxide Modulates Superoxide Release and Peroxynitrite Formation in Human Blood Vessels Hypertension, June 1, 2002; 39(6): 1088 - 1094. [Abstract] [Full Text] [PDF]
|
|