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 alpha(1)-adrenoceptors (alpha(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 beta-hydroxylase(-/-) (DBH(-/-))] or alpha(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(O(2))). 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(-/-) = alpha(1D)-AR(-/-) > alpha(1B)-AR(-/-)). Distal muscularization of small arterioles was also reduced (DBH(-/-) > alpha(1D)-AR(-/-) > alpha(1B)-AR(-/-) mice). Despite these reductions, increases in right ventricular pressure and
hypertrophy were not attenuated in DBH(-/-) and alpha(1B)-AR(-/-) mice. However, hematocrit increased more in these mice, possibly as a consequence of impaired cardiovascular activation that occurs during reduction of Fi(O(2)). In contrast, in alpha(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 alpha(1B)- and alpha(1D)-ARs contributes significantly to
vascular remodeling in hypoxic PH.