Adrenergic catecholamine trophic activity contributes to flow-mediated arterial remodeling

Abstract

Stimulation of alpha1-adrenoceptors (ARs) induces proliferation, hypertrophy, and migration of vascular smooth muscle cells and adventitial fibroblasts in cell and organ culture. In vivo studies have confirmed this direct trophic action and found that endogenous catecholamines contribute to neointimal formation and wall hypertrophy induced by mechanical injury. In murine carotid artery, these effects are mediated by alpha 1B-ARs, whereas alpha 1D-ARs mediate contraction and alpha 1A-ARs are not expressed. Herein, we examined whether catecholamines also contribute to arterial wall growth in a noninjury model, i.e., flow-mediated remodeling. In wild-type mice or mice deficient in norepinephrine and epinephrine synthesis [dopamine beta-hydroxylase knockout (DBH-KO)], all distal branches of the left carotid artery (LC) except the thyroid artery were ligated to reduce flow in the LC and increase flow in the right carotid artery (RC). Twenty-one days later, negative hypertrophic remodeling of the LC [i.e., -20% (decrease) in lumen area, -2% in circumference of the external elastic lamina (CEEL), +98% (increase) in thickness of the intima media, and +71% in thickness for adventitia; P < 0.01 vs. sham ligation] and positive eutrophic remodeling of the RC [+23% in lumen area, +11% in CEEL; P < 0.01 vs. sham ligation] were inhibited in DBH-KO mice [LC: +10% intima media and +3% adventitia; RC: +9% lumen area and +3% CEEL]. This inhibition was associated with reduced proliferation in the RC and reduced apoptosis and leukocyte accumulation in the RC and LC when examined 5 days after ligation. Carotid remodeling in alpha 1D-AR-knockout mice evidenced little or no inhibition, which suggests dependence on alpha 1B-ARs. These findings suggest that catecholamine-induced trophic activity contributes to both flow-mediated negative remodeling and adaptive positive arterial remodeling.

Functional adaptation and remodeling of pulmonary artery in flow-induced pulmonary hypertension

“…These results are consistent with morphological changes detected in media of PA with hypertension. Reported increase in catecholamines-mediated trophic effect (19) and activation of Rho kinase (42) could be the mechanisms responsible for flow-induced vascular smooth muscle hypertrophy, proliferation, and increased reactivity to vasoconstrictors.…”

Inhibitory effect of D1-like and D3dopamine receptors on norepinephrine-induced proliferation in vascular smooth muscle cells

“…Vascular smooth muscle cell (VSMC) proliferation is central to the development of vascular diseases, such as restenosis and atherosclerosis. In addition to the fact that prolonged elevation of plasma catecholamines is a risk factor for vascular diseases, recent reports have shown that catecholamines directly induce hypertrophy of the arterial wall by stimulation of ␣ 1 -adrenoceptors (7,10). Catecholamines in cell and organ culture induce dose-dependent proliferation of VSMCs, and the trophic effect is dependent on the production of reactive oxygen species (5).…”

Normalization of catecholamine production following resection of phaeochromocytoma positively influences carotid vascular remodelling

“…They show that eutrophic (collagen deposition and fibrosis) and hypertrophic (proliferation and migration of smooth muscle cells and of adventitial fibroblasts) remodelling characterizes the damages caused by catecholamines on the vascular wall (1,(4)(5)(6)(7)(8)(9). These observations have also been indirectly confirmed by using a-adrenoceptor antagonists (9)(10)(11)(12)(13) and by experiments in animals submitted to local or systemic sympathetic denervation (14).…”

“…This direct trophic effect of catecholamines, mediated by a-adrenoceptors, concerns an increase in extracellular matrix, with consequent wall fibrosis and eutrophic remodelling. Moreover, in animal models employing balloon injury of the carotid or aorta, an exacerbation of this action may be observed with proliferation, hypertrophy and migration of smooth muscle cells and adventitial fibroblasts, leading to hypertrophic remodelling (1,(4)(5)(6)(7)(8)(9). The direct influence of sympathetic neurotransmitters on vascular wall structure has been supported by studies using a-adrenoceptor antagonists that showed a reduction in proliferation of vascular wall cells and in neointimal growth after vascular injury (9)(10)(11)(12)(13).…”