In vivo gene transfer of prepro-calcitonin gene-related peptide to the lung attenuates chronic hypoxia-induced pulmonary hypertension in the mouse.
BACKGROUND
Calcitonin gene-related peptide (CGRP) is believed to play an important role in maintaining low pulmonary vascular resistance (PVR) and in modulating pulmonary vascular responses to chronic hypoxia; however, the effects of adenovirally mediated gene transfer of CGRP on the response to hypoxia are unknown.


RESULTS
In the present study, an adenoviral vector encoding prepro-CGRP (AdRSVCGRP) was used to examine the effects of in vivo gene transfer of CGRP on increases in PVR, right ventricular mass (RVM), and pulmonary vascular remodeling that occur in chronic hypoxia in the mouse. Intratracheal administration of AdRSVCGRP, followed by 16 days of chronic hypoxia (FIO(2) 0.10), increased lung CGRP and cAMP levels. The increase in pulmonary arterial pressure (PAP), PVR, RVM, and pulmonary vascular remodeling in response to chronic hypoxia was attenuated in animals overexpressing prepro-CGRP, whereas systemic pressure was not altered while in chronically hypoxic mice, angiotensin II and endothelin-1-induced increases in PAP were reduced, whereas decreases in PAP in response to CGRP and adrenomedullin were not changed and decreases in PAP in response to a cAMP phosphodiesterase inhibitor were enhanced by AdRSVCGRP.


CONCLUSIONS
In vivo CGRP lung gene transfer attenuates the increase in PVR and RVM, pulmonary vascular remodeling, and pressor responses in chronically hypoxic mice, suggesting that CGRP gene transfer alone and with a cAMP phosphodiesterase inhibitor may be useful for the treatment of pulmonary hypertensive disorders.
Champion
H C
HC
Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Bivalacqua
T J
TJ
Toyoda
K
K
Heistad
D D
DD
Hyman
A L
AL
Kadowitz
P J
PJ
D000256:Adenoviridae / Q000235:genetics; D053607:Adrenomedullin; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000628:therapy*; D000860:Hypoxia / Q000150:complications* / Q000503:physiopathology; D008168:Lung / Q000378:metabolism*; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011688:Purinones / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology; D020889:Rolipram / Q000494:pharmacology; D015290:Second Messenger Systems / Q000187:drug effects; D014162:Transfection; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000627:therapeutic use; D001616:beta-Galactosidase / Q000032:analysis / Q000096:biosynthesis
D019332:Endothelin-1; D010455:Peptides; D010726:Phosphodiesterase Inhibitors; D015221:Potassium Channels; D011498:Protein Precursors; D011688:Purinones; D011993:Recombinant Fusion Proteins; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C076404:preprocalcitonin gene-related peptide; D053607:Adrenomedullin; D000242:Cyclic AMP; D001616:beta-Galactosidase; C011145:zaprinast; D006152:Cyclic GMP; D015740:Calcitonin Gene-Related Peptide; D020889:Rolipram; D019331:NG-Nitroarginine Methyl Ester