Role of Angiotensin II in the Remodeling Induced by a Chronic Increase in Flow in Rat Mesenteric Resistance Arteries

Abstract

Abstract-Angiotensin II is a potent growth factor involved in arterial wall homeostasis. In resistance arteries, chronic increases in blood flow induce a rise in diameter associated with arterial wall hypertrophy. Nevertheless, the role of angiotensin II in this remodeling is unknown. We investigated the effect of blocking angiotensin II production or receptor activation on flow-induced remodeling of mesenteric resistance arteries. Arteries were ligated in vivo to generate high-flow arteries compared with normal flow (control) vessels located at a distance. Arteries were isolated after 1 week for in vitro analysis. Arterial diameter, media surface, endothelial NO synthase expression, superoxide production, and extracellular signal-regulated kinase 1/2 phosphorylation were higher in high-flow than in control arteries. Angiotensin-converting enzyme inhibition (perindopril) and angiotensin II type 1 receptor blockade (candesartan) prevented arterial wall hypertrophy without affecting diameter enlargement. The nonselective vasodilator hydralazine had no effect on remodeling. Although perindopril and candesartan increased endothelial NO synthase expression in high-flow arteries, hypertrophy remained in rats treated with N G -nitro-L-arginine methyl ester and mice lacking endothelial NO synthase. Perindopril and candesartan reduced oxidative stress in high-flow arteries, but superoxide scavenging did not prevent hypertrophy. Both Tempol and the absence of endothelial NO synthase prevented the rise in diameter in high-flow vessels. Extracellular signal-regulated kinase 1/2 activation in high-flow arteries was prevented by perindopril and candesartan and not by hydralazine. Extracellular signal-regulated kinase 1/2 inhibition in vivo (U0126) prevented hypertrophy in high-flow arteries. Thus, a chronic rise in blood flow in resistance arteries induces a diameter enlargement involving NO and superoxide, whereas hypertrophy was associated with extracellular signal-regulated kinase 1/2 activation by angiotensin II. (Hypertension. 2010;55:109-115.) Key Words: resistance arteries Ⅲ blood flow Ⅲ angiotensin II Ⅲ ERK1/2 Ⅲ shear stress Ⅲ angiotensin I-converting enzyme inhibitors Ⅲ angiotensin II type 1 receptor inhibitor A ngiotensin II is a potent vasoactive hormone involved in the regulation of vascular tone, 1,2 in cell growth and apoptosis, 3 and in cell migration and extracellular matrix deposition. 4 Angiotensin II also has a central role in the functional and structural integrity of the vascular wall and in the pathogenesis of cardiovascular diseases. [5][6][7] Chronic changes in blood flow occur in physiological conditions, such as exercise, pregnancy, or postnatal development, and in pathological conditions, such as arterial occlusive diseases, diabetes mellitus, or hypertension. 1,8 A chronic increase in blood flow induces remodeling of the vascular wall to adapt arterial wall strain to the new hemodynamic conditions, as described in large blood vessels 9 and in small resistance arteries. 1,8 Indeed, in resistance art...

Involvement of angiotensin II in the remodeling induced by a chronic decrease in blood flow in rat mesenteric resistance arteries

“…Interestingly, in a previous work, we showed that in response to a chronic increase in flow, angiotensin II induces hypertrophy (through AT1R) without eliciting any change in diameter, 16 whereas this study shows that in response to a decreased flow, angiotensin II controls the diameter change without obvious effects on wall mass. Thus, in ischemia (with reduced flow in ischemic tissues and a rise in flow in the surrounding tissues), blocking the AT1R might have a doubly beneficial effect, preventing any reduction in diameter in the ischemic zone and reducing hypertrophy in the feeding arteries that are sometimes recruited to vascularize the ischemic tissue.…”

“…As we have previously shown 16 that angiotensin II-induced contraction was mediated by the activation of ERK1/2 in mesenteric RAs, we tested the effect of ERK1/2 blockade on vascular contractility in LF arteries. Indeed, the inhibition of ERK1/2 by PD98059 decreased angiotensin II-induced contraction in NF arteries and suppressed the phenomenon in LF vessels (Figure 6a).…”

“…12,14,15 We have also shown that angiotensin II induces hypertrophy through its type 1 receptor (AT1R) and extracellular signal-regulated kinase (ERK)1/2 activation, without being involved in diameter enlargement, in RAs submitted chronically to increased blood flow. 16 Thus, in response to a chronic rise in flow, diameter increases because of activation of the NO-cGMP pathway, 17 and wall mass increases after activation of AT1R and ERK1/2. 16 However, inward remodeling because of a chronic decrease in flow involves a different mechanism, defined primarily by over activity of the contractile agents because of flow (shear stress) reduction.…”

“…16 Thus, in response to a chronic rise in flow, diameter increases because of activation of the NO-cGMP pathway, 17 and wall mass increases after activation of AT1R and ERK1/2. 16 However, inward remodeling because of a chronic decrease in flow involves a different mechanism, defined primarily by over activity of the contractile agents because of flow (shear stress) reduction.…”

Role of estrogens and age in flow-mediated outward remodeling of rat mesenteric resistance arteries

“…The final step, leading to diameter enlargement, requires a dilator stimulus (17). Flow-mediated outward remodeling is also associated with a compensatory increase in wall mass (11,32) due to ANG II type 1 receptor activation of ERK1/2 (11).…”