The long-term objective of the research proposed in this application is to improve the current understanding of regulation of the pulmonary circulation by humoral factors, including vasoactive peptides. Calcitonin gene-related peptide (CGRP) is an endogenous lung peptide which has been shown to have potent vasodilator activity. It has been hypothesized that CRGP may play a role in the regulation of the pulmonary circulation and that blockade of CGRP receptors exacerbates the increase in pulmonary arterial pressure in chronically hypoxic rats whereas CGRP infusion has a beneficial effect in treating pulmonary hypertension. These observations suggest that strategies that increase lung CGRP levels may be useful in the treatment of pulmonary hypertensive disorders. The transfer of genes that code for the production of vasoactive peptides represents a new potential strategy for the treatment of cardiovascular diseases. It has been shown that gene transfer to the lung can decrease pulmonary vascular resistance and responses, suggesting that gene transfer technology may be applicable to the treatment of pulmonary hypertensive disorders. The investigators therefore hypothesize that adenovirally-mediated transfer of the gene coding for preproCGRP (ADRSVCGRP) may reduce pulmonary vascular resistance and responses to vasoconstrictor agents and may have a beneficial action in a model of pulmonary hypertension. In recent studies they have been able to show that adenovirally-mediated transfer of prepro CGRP increases lung CGRP levels, alters vascular responses, and has a beneficial effect in a model of hypoxia-induced pulmonary hypertension in the mouse. The experiments proposed in this revised application will determine if in vivo delivery of prepro CGRP will alter pulmonary vascular resistance and responses 3, 5, 7, 14, and 21 days after transfection with ADRSVCGRP. The effects of transfection with ADRVSCGRP will be compared in wild type control mice and in CGRP knockout mice. The studies with the CGRP knockout mice will determine if CGRP is playing a role in regulating baseline tone and responses in the pulmonary vascular bed of the mouse. To further test the hypothesis that CGRP has a modulatory role in the response to hypoxia, the experiments in the A2 version of the grant will test the hypothesis that CGRP has a beneficial role in the response to hypoxia by comparing responses to hypobaric hypoxia in wild type control and CGRP knockout mice. It is anticipated that the results of these studies will provide new information on the potential use of in vivo adenovirally-mediated transfer of the gene coding for prepro CGRP in the treatment of, pulmonary hypertensive disorders which are managed with vasodilator therapy and lung transplantation but are often fatal.
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