Submitted on July 24, 2006
Accepted on January 6, 2007
α1-Adrenoceptor-Dependent Vascular Hypertrophy and
Remodeling in Murine Hypoxic Pulmonary Hypertension
James E. Faber1*, Caroline L Szymeczek2, Susanna Cotecchia3, Steven A Thomas4, Akito Tanoue5, Gozoh Tsujimoto6, and Hua Zhang7
1 Department of Cell & Molecular Physiology, University of North Carolina, Chapel Hill,, North Carolina, United States
2 Department of Biology, University of North Carolina, Chapel Hill, North Carolina, United States
3 Institut de Pharmacologie et Toxicologie, Université de Lausanne, Lausanne, Switzerland
4 Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
5 Department of Molecular and Cellular Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan
6 Department of Genomic Drug Discovery Science, Kyoto University, Kyoto , Japan
7 Department of Cell & Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina, United States
* To whom correspondence should be addressed. E-mail: jefaber{at}med.unc.edu.
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 sympatho-excitation, and prolonged stimulation of 
1-adrenoceptors 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, eg injury, altered shear stress and, notably, 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-/-, DH-/-) or 1-adrenoceptors were examined for alterations in PH, cardiac hypertrophy and vascular remodeling after 21 days exposure to normobaric 0.1 FIO2. Decrease in lumen area and increase in wall thickness of arteries were strongly inhibited in knockout mice (order of extent of inhibition: DH-/- = 1D-AR-/- > 1B-AR-/-). Distal muscularization of small arterioles was also reduced (DH-/- > 1D-AR-/- > 1B-AR-/- mice). Despite these reductions, increases in right ventricular pressure and hypertrophy were not attenuated in DH-/- and 1B-AR-/- mice. However, hematocrit increased more in these mice, possibly as consequence of impaired cardiovascular activation that occurs during reduction of FIO2. In contrast, in 1D-AR-/- mice where hematocrit increased the same as wild type, right ventricular pressure was reduced. These data suggest that catecholamine stimulation of 1B- and 1D-ARs contribute significantly to vascular remodeling in hypoxic pulmonary hypertension.
