title: Targeting endothelial cells with adenovirus expressing nitric oxide synthase prevents elevation of blood pressure in stroke-prone spontaneously hypertensive rats.
abstract: Local adenoviral (Ad)-mediated gene transfer to the carotid artery of the stroke-prone spontaneously hypertensive rat (SHRSP) is successful in improving endothelial function. Here we explored the potential of systemic delivery of Ad encoding endothelial nitric oxide synthase (AdeNOS) to prevent elevation of blood pressure in the SHRSP using both nontargeted and vector targeting approaches. Systemic administration of nontargeted AdeNOS failed to modify the rise in blood pressure in SHRSP when administered during the 12th week of age (n = 5, P = 0.088, F = 3.0), an effect likely to result from sequestration of Ad by the liver. Rerouting Ad transduction using a bispecific antibody (anti-ACE/anti-Ad capsid, Fab9B9) that blocks Ad binding to the coxsackie and adenovirus receptor and simultaneously retargets AdeNOS to the angiotensin-converting enzyme resulted in efficient eNOS overexpression in the lung vasculature and a sustained hypotensive effect (n = 5, P = 0.007, F = 7.9). This study highlights the importance of vector targeting to achieve therapeutic gain and represents the first such study in cardiovascular gene therapy.
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G11 6NT, Scotland, UK.
authors.forename: William H
authors.initials: WH
authors.lastname: Miller
authors.forename: M Julia
authors.initials: MJ
authors.lastname: Brosnan
authors.forename: Delyth
authors.initials: D
authors.lastname: Graham
authors.forename: Campbell G
authors.initials: CG
authors.lastname: Nicol
authors.forename: Ian
authors.initials: I
authors.lastname: Morecroft
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.forename: Sergei M
authors.initials: SM
authors.lastname: Danilov
authors.forename: Paul N
authors.initials: PN
authors.lastname: Reynolds
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
authors.forename: Anna F
authors.initials: AF
authors.lastname: Dominiczak
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D042783:Endothelial Cells; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006973:Hypertension / Q000517:prevention & control*; D048289:Imidazolidines; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007150:Immunohistochemistry; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D019323:omega-N-Methylarginine
chemical_list: D048289:Imidazolidines; D007140:Immunoglobulin Fab Fragments; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase; D007703:Peptidyl-Dipeptidase A