Effects of Exogenous VEGF on Development of Experimental Pulmonary Hypertension and Endotheliumdependent Relaxation

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In addition to its well-known angiogenic properties, VEGF has been shown to protect against endothelial vascular injury and to improve endothelial function. Our previous finding of impaired endothelium-dependent relaxation in chronic hypoxic pulmonary hypertension [1] invited an investigation of whether lung VEGF overexpression can protect against hypoxic pulmonary hypertension and alter the development of pulmonary vascular remodeling.

Gene therapy may be a valuable therapeutic approach in pulmonary hypertension. Several studies using intratracheal administration of adeno-virus vectors have shown that transgene expression is mainly located in epithelial cells [15]. Using this route of administration, previous studies demonstrated that adenoviral-mediated gene transfer of human endothelial nitric oxide synthase (eNOS) in rats was associated with a reduction in acute pulmonary vasoconstriction [17]. We therefore reasoned that overexpression of a secreted and diffusible form of VEGF (VEGF165) in epithelial cells following adenoviral-mediated gene transfer may affect endothelial cell behavior and protect against pulmonary vascular remodeling during development of hypoxic pulmonary hypertension. To investigate this hypothesis, we used a previously described adenovirus vector containing an expression cassette with the cytomegalovirus (CMV) early/intermediate promoter/enhancer driving the human VEGF165 cDNA (Ad.VEGF) [24].

We evaluated the efficiency of gene transfer after a single intratracheal instillation of Ad.VEGF by measuring levels of VEGF protein in broncho-alveolar fluid and serum after various doses of the adenovirus vector and at various times after the instillation [28]. We also evaluated the effect of Ad.VEGF on pulmonary vessel permeability by measuring the extravascular accumulation of radiolabeled albumin corrected for lung blood weight. In the second part of the study, we assessed pulmonary hemodynamics, right ventricular hypertrophy and pulmonary vascular remodeling in rats pre-treated with intratracheal administration of Ad.VEGF two days before the start of a two-week exposure to normoxia or hypoxia. Finally, to investigate the mechanisms of the protective effect of Ad.VEGF on the development of hypoxic pulmonary hypertension, we measured eNOS activity in lung tissue and examined pulmonary vasoreactivity using isolated lungs from normoxic and chronically hypoxic rats pretreated with Ad.VEGF.

We found that adenoviral-mediated lung VEGF overexpression, which had no effect on the pulmonary circulation during normoxia, protected rats exposed to chronic hypoxia against development of pulmonary hypertension [28]. Values were lower for pulmonary arterial pressure, right ventricular hypertrophy and distal vessel muscularization in hypoxic rats pretreated with Ad.VEGF compared to rats pretreated with the control vector Ad.Null. Our results also suggest that this protective effect of VEGF on the pulmonary circulation during exposure to chronic hypoxia was, at least partially, related to an improvement in endothelial function. Indeed, Ad.VEGF pretreatment was associated with increased lung eNOS activity, partial restoration of the vasodilator response to the endothelium-dependent agent ionophore A23187 and with marked blunting of endothelin-1-induced vasoconstriction.

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