α₁-Adrenoceptor stimulation directly induces growth of vascular wall in vivo

Abstract

Previous studies suggesting that norepinephrine is directly trophic for the vascular wall have been confounded by concomitant hemodynamic disturbances. Herein, a microcatheter connected to an osmotic minipump was implanted adjacent to the rat carotid for 2-wk perivascular suffusion of agents at systemic levels ϳ1,000 times below the threshold for altering arterial pressure. Norepinephrine decreased lumen and adventitial areas and circumference by 10, 14, and 5%, respectively (all P Ͻ 0.05); a nonsubtype-specific ␣ 1-adrenoceptor (AR) antagonist had no effect. When begun at the time of balloon injury, 2-wk norepinephrine increased lumen loss by 45%, increased neointimal area by 64% and collagen content by 33%, and reduced vessel circumference by 5% (all P Ͻ 0.05). ␣ 1-AR antagonists decreased neointimal area by 33% (all P Ͻ 0.05). ␣ 1A-AR antagonist reduced lumen loss by 70%, neointimal area by 54%, circumference decline by 84%, and adventitial thickening by 87% (all P Ͻ 0.05), whereas ␣ 1B-, ␣1D-, ␣2-and ␤-AR antagonists were without effect. These are the first in vivo studies demonstrating that norepinephrine is directly trophic for the vascular wall and augments injury-induced intimal lesion growth. artery; smooth muscle; adventitia; injury; adrenergic VASCULAR HYPERTROPHY and remodeling are adaptive structural changes in response to sustained increases in arterial pressure or altered shear stress that favor restoration of normal physiological regulation. On the other hand, excessive wall growth, fibrosis, and inward or inadequate outward remodeling cause failure of surgical procedures (e.g., restenosis after angioplasty/ stent, atherectomy, and bypass grafting) and underlie diseases such as atherosclerosis, pulmonary hypertension, and accelerated arteriosclerosis (31,35). Thus the mechanisms regulating growth of vascular wall cells are under intense investigation. Besides the vasoactive actions of norepinephrine (NE), there is growing evidence that NE may be a trophic mediator for vascular smooth muscle cells (SMCs) and adventitial fibroblasts (AFBs). In vivo studies using surgical or systemic sympathetic denervation (16), systemic infusion of catecholamines (7, 21), or ␣-adrenoceptor (AR) antagonists (20), as well as positive correlation of plasma catecholamines with wall hypertrophy and stiffness (8) and severity of atherosclerosis (22) in humans, suggest that NE may have direct trophic effects on the normal and diseased vascular wall. Moreover, in the ballooninjured rat and rabbit carotid, chronic systemic ␣ 1 -AR antagonists reduced cell proliferation, neointimal growth, and restenosis by at least 50% (14,18,30,34). ␣ 1 -AR antagonists also attenuated angiotensin II-induced DNA synthesis (33) and atherogenesis (26,29). However, interpretation of these past in vivo studies is complicated by concomitant hemodynamic disturbances that, themselves, have trophic effects. For example, chemical or immunological systemic denervation and systemic ␣-AR antagonists cause significant hypotension and humoral changes. A...

Sympathetic Activation in Chronic Renal Failure

“…60 Accelerated atherosclerosis, vasoconstriction, and proliferation of smooth muscle cells and adventitial fibroblasts in the vessel wall are further consequences of sympathetic activation related to progression of renal damage. 61,62 Norepinephrine exerts trophic effects on cardiac myocytes, and recent investigations demonstrated that cardiac sympathetic activity is related to left ventricular hypertrophy in patients with essential hypertension. 63 Sympathetic activation and vagal withdrawal are closely linked to cardiac arrhythmias, 64 which, in concert with the aforementioned factors, is partly responsible for the high rate of sudden cardiac death in patients with CRF.…”

Vascular Damages in Rats Immunized by α1-Adrenoceptor Peptides

“…Previous reports identified that treatments with norepinephrine (NE) could induce cardiac remodeling in rats (9,10), and increased sympathetic stimulation of the arteries might contribute to the arterial remodeling, which would be induced by α 1 -adrenoceptor-dependent proliferation, hypertrophy, and migration of vascular smooth muscle cells (VSMCs) and adventitial fibroblasts (11,12). These findings suggest that NE may contribute to adverse structural remodeling in hypertension.…”

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).…”