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

Abstract

Blood flow reduction induces inward remodeling of resistance arteries (RAs). This remodeling occurs in ischemic diseases, diabetes and hypertension. Nonetheless, the effect of flow reduction per se, independent of the effect of pressure or metabolic influences, is not well understood in RA. As angiotensin II is involved in the response to flow in RA, we hypothesized that angiotensin II may also be involved in the remodeling induced by a chronic flow reduction. We analyzed the effect of angiotensin I-converting enzyme inhibition (perindopril) and angiotensin II type 1 receptor blockade (candesartan) on inward remodeling induced by blood flow reduction in vivo in rat mesenteric RAs (low flow (LF) arteries). After 1 week, diameter reduction in LF arteries was associated with reduced endothelium-dependent relaxation and lower levels of eNOS expression. Superoxide production and extracellular signal-regulated kinases 1/2 (ERK1/2 phosphorylation were higher in LF than in normal flow arteries. Nevertheless, the absence of eNOS or superoxide level reduction (tempol or apocynin) did not prevent LF remodeling. Perindopril and candesartan prevented inward remodeling in LF arteries. Contractility to angiotensin II was reduced in LF vessels by perindopril, candesartan and the ERK1/2 blocker PD98059. ERK1/2 activation (ratio phospho-ERK/ERK) was higher in LF arteries, and this activation was prevented by perindopril and candesartan. ERK1/2 inhibition in vivo (U0126) prevented LF-induced diameter reduction. Thus, inward remodeling because of blood flow reduction in mesenteric RA depends on unopposed angiotensin II-induced contraction and ERK1/2 activation, independent of superoxide production. These findings might be of importance in the treatment of vascular disorders.

Persistent effect of early, brief angiotensin-converting enzyme inhibition on segmental pressure dependency of aortic stiffness in spontaneously hypertensive rats

“…Previous studies showed that ACEi at a critical time window before the onset of hypertension prevents blood pressure (BP) from reaching fully hypertensive levels in adult SHR, an effect that persists even after withdrawal of treatment [2,3]. These chronic changes in BP have been suggested to be due to a reduction in flow-dependent adaptive remodelling of the vascular wall [4,5], both in large arteries [6][7][8] and in smaller resistance arteries [9].…”

Heme Oxygenase 1 Is Differentially Involved in Blood Flow–Dependent Arterial Remodeling

“…19,26,27 These diameter changes aim to restore basal tensile and shear stress levels. It is important to note that, in this model, HF and LF arteries are compared with NF arteries obtained at the same time point from the same animal and subsequently submitted to comparable experimental and physiological conditions.…”

“…26 Meanwhile, MCP-1 expression in vascular cells was increased 2 days after ligation by a mechanism probably implicating the renin-angiotensin system. 40 MCP-1 attracts macrophages, implicated in the formation of ROS, most probably via NADPH oxidase in LF arteries.…”

The Role of Reactive Oxygen Species in Microvascular Remodeling

“…Although angiotensin II is usually associated with vasoconstriction and hypertension, ROS and angiotensin II-dependent signaling are also associated with the outward remodeling induced by high-flow conditions in mesenteric resistance arteries [ 136 , 138 ]. Multiple studies have shown the effects of high or low flow conditions in resistance arteries [ 39 , 133 , 134 , 135 , 142 , 143 ]. High flow induces outward hypertrophic remodeling, while low flow induces inward hypotrophic remodeling.…”

“…It appears that superoxide mediates the luminal enlargement effect of high flow, while angiotensin II mediates the hypertrophic effect through extracellular-signal-regulated kinases (ERK)1/2 activation [ 136 ]. In contrast, angiotensin II-dependent constriction appears to mediate low flow-induced inward remodeling with only a marginal effect of superoxide on the cross-sectional area of the wall [ 133 ]. It is believed that hemodynamics and the local signaling environment, in particular the local production of vasodilators and vasoconstrictors, affect the contractile and synthetic state of cells within the vascular wall and thus guide the type of remodeling [ 142 ].…”