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₁-Adrenoceptor-dependent vascular hypertrophy and remodeling in murine hypoxic pulmonary hypertension

¹Department of Cell and Molecular Physiology, School of Medicine, and ²Department of Biology, University of North Carolina, Chapel Hill, North Carolina; ³Départment de Pharmacologie et de Toxicologie, Université de Lausanne, Switzerland; ⁴Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania; ⁵Department of Molecular and Cellular Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan; and ⁶Department of Genomic Drug Discovery Science, Kyoto University, Kyoto, Japan

Submitted 24 July 2006 ; accepted in final form 6 January 2007

Excessive proliferation of vascular wall cells underlies the development of elevated vascular resistance in hypoxic pulmonary hypertension (PH), but the responsible mechanisms remain unclear. Growth-promoting effects of catecholamines may contribute. Hypoxemia causes sympathoexcitation, and prolonged stimulation of ₁-adrenoceptors (₁-ARs) induces hypertrophy and hyperplasia of arterial smooth muscle cells and adventitial fibroblasts. Catecholamine trophic actions in arteries are enhanced when other conditions favoring growth or remodeling are present, e.g., injury or altered shear stress, in isolated pulmonary arteries from rats with hypoxic PH. The present study examined the hypothesis that catecholamines contribute to pulmonary vascular remodeling in vivo in hypoxic PH. Mice genetically deficient in norepinephrine and epinephrine production [dopamine -hydroxylase^–/– (DBH^–/–)] or ₁-ARs were examined for alterations in PH, cardiac hypertrophy, and vascular remodeling after 21 days exposure to normobaric 0.1 inspired oxygen fraction (FI_O2). A decrease in the lumen area and an increase in the wall thickness of arteries were strongly inhibited in knockout mice (order of extent of inhibition: DBH^–/– = _1D-AR^–/– > _1B-AR^–/–). Distal muscularization of small arterioles was also reduced (DBH^–/– > _1D-AR^–/– > _1B-AR^–/– mice). Despite these reductions, increases in right ventricular pressure and hypertrophy were not attenuated in DBH^–/– and _1B-AR^–/– mice. However, hematocrit increased more in these mice, possibly as a consequence of impaired cardiovascular activation that occurs during reduction of FI_O2. In contrast, in _1D-AR^–/– mice, where hematocrit increased the same as in wild-type mice, right ventricular pressure was reduced. These data suggest that catecholamine stimulation of _1B- and _1D-ARs contributes significantly to vascular remodeling in hypoxic PH.

vascular smooth muscle; adrenergic receptors; hypoxia

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