Expression and function of recombinant endothelial nitric oxide synthase gene in canine basilar artery after experimental subarachnoid hemorrhage.

BACKGROUND AND PURPOSE Gene transfer with recombinant viral vectors encoding vasodilator proteins may be useful in therapy of cerebral vasospasm after subarachnoid hemorrhage (SAH). Relaxations mediated by nitric oxide are impaired in cerebral arteries affected by SAH. The present study was designed to determine the effect of SAH on the efficiency of ex vivo adenovirus-mediated gene transfer to canine basilar arteries and to examine whether expression of recombinant endothelial nitric oxide synthase (eNOS) gene may have functional effects on vasomotor reactivity of spastic arteries affected by SAH. METHODS Replication-deficient recombinant adenovirus vectors encoding bovine eNOS (AdCMVeNOS) and Escherichia coli beta-galactosidase (AdCMVbeta-Gal) genes were used for ex vivo gene transfer. Rings of basilar arteries obtained from control dogs and dogs exposed to SAH were incubated with the vectors in minimum essential medium. Twenty-four hours after gene transfer, expression and function of the recombinant genes were evaluated by (1) histochemical or immunohistochemical staining, (2) beta-galactosidase protein measurement, and (3) isometric tension recording. RESULTS Transduction with AdCMVbeta-Gal and AdCMVeNOS resulted in the expression of recombinant beta-galactosidase and eNOS proteins mostly in the vascular adventitia. The expression of beta-galactosidase protein was approximately 2-fold higher in SAH arteries than in normal arteries. Endothelium-dependent relaxations caused by bradykinin and substance P were suppressed in SAH arteries. The relaxations to bradykinin were significantly augmented in both normal and SAH arteries after AdCMVeNOS transduction but not after AdCMVbeta-Gal transduction. The relaxations to substance P were augmented by AdCMVeNOS transduction only in normal arteries. Bradykinin and substance P caused relaxations even in endothelium-denuded arteries, when the vessels were transduced with AdCMVeNOS. These endothelium-independent (adventitia-dependent) relaxations to bradykinin observed after AdCMVeNOS transduction were similar between normal and SAH arteries, whereas those to substance P were significantly reduced in SAH arteries compared with normal arteries. CONCLUSIONS These results suggest that expression of recombinant proteins after adenovirus-mediated gene transfer may be enhanced in cerebral arteries affected by SAH and that successful eNOS gene transfer to spastic arteries can at least partly restore the impaired nitric oxide-mediated relaxations through local (adventitial) production of nitric oxide.

[1]  Leslie A. Smith,et al.  Adventitial Expression of Recombinant Endothelial Nitric Oxide Synthase Gene Reverses Vasoconstrictor Effect of Endothelin-1 , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[2]  Z. Katušić,et al.  Adventitial expression of recombinant eNOS gene restores NO production in arteries without endothelium. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[3]  R. Morishita,et al.  Decoy administration of NF-kappaB into the subarachnoid space for cerebral angiopathy. , 1998, Human gene therapy.

[4]  D. Heistad,et al.  Regulation of the cerebral circulation: role of endothelium and potassium channels. , 1998, Physiological reviews.

[5]  Leslie A. Smith,et al.  Effects of in vivo adventitial expression of recombinant endothelial nitric oxide synthase gene in cerebral arteries. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[6]  D. Escande,et al.  Vasomotor dysfunction early after exposure of normal rabbit arteries to an adenoviral vector. , 1997, Human gene therapy.

[7]  B. Davidson,et al.  Gene transfer to cerebral blood vessels after subarachnoid hemorrhage. , 1997, Stroke.

[8]  Z. Katušić,et al.  Expression and function of recombinant endothelial nitric oxide synthase gene in canine basilar artery. , 1997, Circulation research.

[9]  Y. Ninomiya,et al.  Inhibition of vascular contraction by intracisternal administration of preproendothelin-1 mRNA antisense oligoDNA in a rat experimental vasospasm model. , 1996, Journal of neurosurgery.

[10]  K. Kanamaru,et al.  Effects of nitroglycerin on vasospasm and cyclic nucleotides in a primate model of subarachnoid hemorrhage. , 1996, Stroke.

[11]  R. Macdonald,et al.  Changes in endothelial nitric oxide synthase mRNA during vasospasm after subarachnoid hemorrhage in monkeys. , 1996, Neurosurgery.

[12]  D. Heistad,et al.  Gene therapy for cerebral vascular disease. , 1996, Stroke.

[13]  D. Collen,et al.  Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats. , 1996, The Journal of clinical investigation.

[14]  S. Snyder,et al.  Loss of nitric oxide synthase immunoreactivity in cerebral vasospasm. , 1996, Journal of neurosurgery.

[15]  A. Yao,et al.  Heterogeneity of adenovirus-mediated gene transfer in cultured thoracic aorta and renal artery of rats. , 1995, Hypertension.

[16]  P. Libby,et al.  Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia. , 1995, The Journal of clinical investigation.

[17]  B. Thompson,et al.  Effect of intracarotid nitric oxide on primate cerebral vasospasm after subarachnoid hemorrhage. , 1995, Journal of neurosurgery.

[18]  B. Davidson,et al.  Adenovirus-mediated gene transfer in vivo to cerebral blood vessels and perivascular tissue. , 1995, Circulation research.

[19]  Y. Kaneda,et al.  Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[20]  E. Nabel,et al.  Gene therapy for cardiovascular disease. , 1995, Circulation.

[21]  Von der Leyen Gene therapy inhibiting neointimal vascular lesion , 1995 .

[22]  D. Spector,et al.  [3] Construction and isolation of recombinant adenoviruses with gene replacements , 1995 .

[23]  K. Sugita,et al.  Combined effect of L-arginine and superoxide dismutase on the spastic basilar artery after subarachnoid hemorrhage in dogs. , 1994, Journal of neurosurgery.

[24]  F. Faraci,et al.  Nitric Oxide and the Cerebral Circulation , 1994, Stroke.

[25]  T. Kubota,et al.  The Kinetics of Lymphocyte Subsets and Macrophages in Subarachnoid Space After Subarachnoid Hemorrhage in Rats , 1993, Stroke.

[26]  J. Milde,et al.  Subarachnoid Hemorrhage and Endothelial L‐Arginine Pathway in Small Brain Stem Arteries in Dogs , 1993, Stroke.

[27]  E. Oldfield,et al.  Is vasospasm related to proliferative arteriopathy? , 1992, Journal of neurosurgery.

[28]  R. Macdonald,et al.  A review of hemoglobin and the pathogenesis of cerebral vasospasm. , 1991, Stroke.

[29]  本郷 一博 Subarachnoid hemorrhage inhibition of endothelium-derived relaxing factor in rabbit basilar artery , 1990 .

[30]  D. Cook,et al.  Pharmacological studies on relaxation of spastic primate cerebral arteries in subarachnoid hemorrhage. , 1989, Journal of neurosurgery.

[31]  N. Toda,et al.  Endothelium-dependent and -independent responses to vasodilators of isolated dog cerebral arteries. , 1988, Stroke.

[32]  K. Hongo,et al.  Subarachnoid hemorrhage inhibition of endothelium-derived relaxing factor in rabbit basilar artery. , 1988, Journal of neurosurgery.

[33]  J. T. Shepherd,et al.  Endothelium-dependent contraction to stretch in canine basilar arteries. , 1987, The American journal of physiology.

[34]  J. Torner,et al.  Impairment of endothelium-dependent vasodilation induced by acetylcholine and adenosine triphosphate following experimental subarachnoid hemorrhage. , 1987, Stroke.

[35]  B. Weir,et al.  Electron microscopy of simian cerebral arteries after subarachnoid hemorrhage and after the injection of horseradish peroxidase. , 1986, Neurosurgery.

[36]  J. T. Shepherd,et al.  Oxytocin causes endothelium-dependent relaxations of canine basilar arteries by activating V1-vasopressinergic receptors. , 1986, The Journal of pharmacology and experimental therapeutics.

[37]  N. Kassell,et al.  Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. , 1985, Stroke.

[38]  R. R. Smith,et al.  Arterial wall changes in early human vasospasm. , 1985, Neurosurgery.