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 im portant role in maintaining low pulmonary vascular resistance (PVR) and in modulating pulmonary vascular responses to chronic hypoxia; however, the ef fects of adenovirally mediated gene transfer of CGRP on the response to hyp oxia are unknown. Methods and Results-In the present study, an adenoviral vector encoding pre pro-CGRP (AdRSVCGRP) was used to examine the effects of in vivo gene transf er of CGRP on increases in PVR, right ventricular mass (RVM), and pulmonary vascular remodeling that occur in chronic hypoxia in the mouse. Intratrach eal administration of AdRSVCGRP, followed by 16 days of chronic hypoxia (FI O2 0.10), increased lung CGRP and cAMP levels. The increase in pulmonary ar terial pressure (PAP), PVR, RVM, and pulmonary vascular remodeling in respo nse to chronic hypoxia was attenuated in animals overexpressing prepro-CGRP , whereas systemic pressure was not altered while in chronically hypoxic mi ce, angiotensin II and endothelin-1-induced increases in PAP were reduced, whereas decreases in PAP in response to CGRP and adrenomedullin were not ch anged and decreases in PAP in response to a cAMP phosphodiesterase inhibito r were enhanced by AdRSVCGRP, Conclusions-In vivo CGRP lung gene transfer attenuates the increase in PVR and RVM, pulmonary vascular remodeling, and presser responses in chronicall y hypoxic mice, suggesting that CGRP gene transfer alone and with a cAMP ph osphodiesterase inhibitor may be useful for the treatment of pulmonary hype rtensive disorders.