Activation of AT ₂ Receptors by Endogenous Angiotensin II Is Involved in Flow-Induced Dilation in Rat Resistance Arteries

Abstract

Abstract-Pressure-induced tone (myogenic, MT) and flow (shear stress)-induced dilation (FD) are potent modulators of resistance artery tone. We tested the hypothesis that locally produced angiotensin II interacts with MT and FD. Rat mesenteric resistance arteries were perfused in situ. Arterial diameter was measured by intravital microscopy after a bifurcation on 2 distal arterial branches equivalent in size (150 m, nϭ7 per group). One was ligated distally and thus submitted to pressure only (MT, no FD). The second branch was submitted to flow and pressure (MT and FD). The difference in diameter between the 2 vessels was considered to be FD. Flow-diameter-pressure relationship was established in the absence and then in the presence of 1 of the following agents. In the nonligated segment (MTϩFD), angiotensin II type 1 (AT 1 ) receptor blockade (losartan) had no significant effect, whereas angiotensin II type 2 (AT 2 ) receptor blockade (PD123319) or saralasin (AT 1 ϩAT 2 blocker) decreased the diameter significantly, by 9Ϯ1 and 10Ϯ0.8 m, respectively. Angiotensin II in the presence of losartan increased the diameter by 18Ϯ0.6 m (inhibited by PD123319). PD123319 or saralasin had no effect after NO synthesis blockade or after endothelial disruption. In the arterial segment ligated distally (MT only), AT 1 or AT 2 receptor blockade had no significant effect. AT 2 -dependent dilation represented 20% to 39% of FD (shear stress from 22 to 37 dyn/cm 2 ), and AT 2 -receptor mRNA was found in mesenteric resistance arteries. Thus, resistance arterial tone was modulated in situ by locally produced angiotensin II, which might participate in flow-induced dilation through endothelial AT 2 receptor activation of NO release. Key Words: blood vessels Ⅲ myogenic Ⅲ arteries Ⅲ stress, mechanical Ⅲ angiotensin II Ⅲ bradykinin F low (shear stress)-induced vasodilation and pressure (tensile stress)-induced tone (myogenic tone) play a key role in the control of vascular tone. [1][2][3][4][5][6] In resistance arteries, pressure or stretch induces myogenic tone, 6 -8 which is opposed by flow-induced dilation, in vitro as well as in vivo. 3,5,6,8,9 Whereas myogenic tone is mainly independent of endothelial factors, 6,8 shear stress has been widely shown to induce the release of endothelium-derived vasoactive agents. 1,4,5,10,11 The local tissue renin-angiotensin system 12-14 is another potent regulator of vascular tone. At physiological concentrations, angiotensin II amplifies agonist-induced contractions. [13][14][15] Angiotensin II also activates nitric oxide (NO) production by vascular endothelial cells through angiotensin II type 1 receptor (AT 1 ) activation 16 or through angiotensin II type 2 (AT 2 ) receptor activation. 17,18 Although no relation between flow-induced dilation and angiotensin II is known as yet, angiotensin II production may be activated by stretch in cardiac myocytes. 19.20 Moreover, in the aorta, stretch and angiotensin II synergistically activate DNA and protein synthesis. 21 Nevertheless, the role of angiotensin...

Involvement of Metalloproteinases 2/9 in Epidermal Growth Factor Receptor Transactivation in Pressure-Induced Myogenic Tone in Mouse Mesenteric Resistance Arteries

“…9 MT is also influenced by neurohormonal mechanisms via activation of signal transduction pathways that regulate VSMC contraction and growth. 5,10,11 For example, low concentrations of Ang II potentiate MT, whereas higher Ang II concentrations induce contraction of resistance arteries. 12,13 These contractile effects of Ang II are attributed largely to angiotensin II type I receptor (AT 1 -R) activation.…”

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

“…Vasoconstrictor tone in RAs relies in large part on locally produced angiotensin II. 12,15,42,43 In LF arteries, angiotensin II-induced contraction was strongly reduced in rats treated with perindopril or candesartan, but not in rats treated with hydralazine. In addition, both AT1R and AT2R expression levels were higher in LF as compared with NF arteries.…”

“…In mesenteric RAs, we have previously shown that acute stimulation of the endothelium by flow (shear stress) induces vasodilation, which is modulated by the local production of angiotensin II. 12,13 Furthermore, we found that angiotensin II activation through type 2 receptor (AT2R) activation is directly involved in flowmediated dilation. 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.…”

“…12,13 Furthermore, we found that angiotensin II activation through type 2 receptor (AT2R) activation is directly involved in flowmediated dilation. 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.…”

Role of angiotensin II receptor subtypes in porcine basilar artery: Functional, radioligand binding, and cell culture studies

“…In general, AT 2 receptors are predominant in the fetus; however, after birth the expression of AT 2 receptors is restricted to some regions and AT 1 receptors become predominant (Matsubara, 1998;Horiuchi et al, 1999). The AT 1 receptor is concerned with vasoconstriction in various arteries, whereas the AT 2 receptor is concerned with vasorelaxation in the uterine (McMullen et al, 1999;Hannan et al, 2003), mesenteric (Matrougui et al, 1999;Touyz et al, 1999;Matrougui et al, 2000), and cerebral (Tsutsumi and Saavedra, 1991) arteries. However, the role of the AT 2 receptor remains unclear.…”