Gene transfer of calcitonin gene-related peptide to cerebral arteries.
Overexpression of calcitonin gene-related peptide (CGRP), an extremely potent vasodilator, to blood vessels is a possible strategy for prevention of vasospasm. We constructed an adenoviral vector that encodes prepro-CGRP (Adprepro-CGRP) and examined the effects of gene transfer on cultured cells and cerebral arteries. Transfection of Adprepro-CGRP to Cos-7 and NIH-3T3 cells increased CGRP-like immunoreactivity in media and produced an increase in cAMP in recipient cells. Five days after injection of Adprepro-CGRP into the cisterna magna of rabbits, the concentration of CGRP-like immunoreactivity increased by 93-fold in cerebrospinal fluid. In basilar artery, cAMP increased by 2.3-fold after Adprepro-CGRP compared with a control adenovirus. After transfection of Adprepro-CGRP, contraction of basilar artery in vitro to histamine and serotonin was attenuated, and relaxation to an inhibitor of cyclic nucleotide phosphodiesterase 3-isobutyl-1-methylxanthine was augmented compared with nontransduced arteries or arteries transfected with a control gene. Altered vascular responses were restored to normal by pretreatment with a CGRP(1) receptor antagonist CGRP-(8-37). Thus gene transfer of prepro-CGRP in vivo overexpresses CGRP in cerebrospinal fluid and perivascular tissues and modulates vascular tone. We speculate that this approach may be useful in prevention of vasospasm after subarachnoid hemorrhage.
Toyoda
K
K
Department of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa College of Medicine, and Veterans Administration Medical Center, Iowa City, Iowa 52242, USA.
Faraci
F M
FM
Russo
A F
AF
Davidson
B L
BL
Heistad
D D
DD
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D016475:3T3 Cells; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000378:metabolism; D019556:COS Cells; D015740:Calcitonin Gene-Related Peptide / Q000134:cerebrospinal fluid / Q000138:chemical synthesis / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D002536:Cerebral Arteries / Q000502:physiology*; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D018014:Gene Transfer Techniques; D006632:Histamine / Q000494:pharmacology; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics; D011817:Rabbits; D012701:Serotonin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000134:cerebrospinal fluid / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D011498:Protein Precursors; D014665:Vasodilator Agents; C076404:preprocalcitonin gene-related peptide; D012701:Serotonin; D006632:Histamine; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide; D015056:1-Methyl-3-isobutylxanthine