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Α1-Adrenergic receptors mediate combined signals initiated by mechanical stretch stress and norepinephrine leading to accelerated mouse vein graft atherosclerosis 

Published byΓιώργος Χατζηιωάννου Modified over 5 years ago

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Presentation on theme: "Α1-Adrenergic receptors mediate combined signals initiated by mechanical stretch stress and norepinephrine leading to accelerated mouse vein graft atherosclerosis "— Presentation transcript:

1 α1-Adrenergic receptors mediate combined signals initiated by mechanical stretch stress and norepinephrine leading to accelerated mouse vein graft atherosclerosis  Shuying Liu, MD, PhD, Yuhuang Li, MD, PhD, Zhengyu Zhang, MD, PhD, Fukang Xie, PhD, Qingbo Xu, MD, PhD, Xi Huang, MD, PhD, Jintao Huang, BS, Chaohong Li, PhD  Journal of Vascular Surgery  Volume 57, Issue 6, Pages e3 (June 2013) DOI: /j.jvs Copyright © 2013 Society for Vascular Surgery Terms and Conditions

2 Fig 1 A-E, Differential expression of α1-adrenergic receptor (α1-AR) subtypes and norepinephrine (NE)-induced extracellular signal-regulated kinase (ERK) activation in vascular smooth muscle cells (VSMCs). A, The expression level of mRNAs of α1A-ARs, α1B-ARs, α1D-ARs in VSMCs as detected by real-time quantitative polymerase chain reaction (qPCR). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was served as an internal control. B, NE dose-dependently induces ERK activation in VSMCs, which is dose-dependently inhibited by prazosin (D). C and E, Statistical results of phosphorylated ERK (pERK) levels of B and D from three independent experiments. β-actin was served as internal control. *P < .05 vs negative control (NC); #P < .05 vs NE. Journal of Vascular Surgery  , e3DOI: ( /j.jvs ) Copyright © 2013 Society for Vascular Surgery Terms and Conditions

3 Fig 2 A-H, Mechanical stretch induces Gαq translocation from membrane to cytosol and extracellular signal-regulated kinase (ERK) phosphorylation in vascular smooth muscle cells (VSMCs) partially inhibited by prazosin. A, The cyclic stretch stress (SS)-induced VSMCs Gαq translocation from membrane to cytosol in a time-dependent manner. RAGE and β-actin were used as internal controls of membrane-Gαq and cytosol-Gαq. C, Prazosin partially inhibited SS-induced Gαq translocation. E, SS-induced VSMCs ERK phosphorylation in an elongation-dependent manner, which can be dose-dependently inhibited by prazosin (G). B, D, F, and H show statistical results of A, C, E, and G from three independent experiments. Pan-ERKs or β-actin served as internal control. *P < .05 vs negative control (NC); #P < .05 vs SS without prazosin. Journal of Vascular Surgery  , e3DOI: ( /j.jvs ) Copyright © 2013 Society for Vascular Surgery Terms and Conditions

4 Fig 3 A and B, α1-Adrenergic receptors (α1-ARs) partially mediate additive activation of extracellular signal-regulated kinases (ERKs) in vascular smooth muscle cells (VSMCs) initiated by combined treatment of cyclic stretch stress (SS) and norepinephrine (NE). A, The additive activation of ERKs in VSMCs stimulated by combined treatment with cyclic SS (10% elongation for 10 minutes) and NE (10−7 M, 10 minutes) with or without prazosin (Praz) (10−7 M). B, Statistical results of phosphorylated ERK (pERK) levels of A from three independent experiments. β-actin served as internal control. *P < .05 vs negative control (NC); aP < .05 vs NE; bP < .05 vs SS; cP < .05 vs SS+NE; $P < .05 vs SS+NE. Journal of Vascular Surgery  , e3DOI: ( /j.jvs ) Copyright © 2013 Society for Vascular Surgery Terms and Conditions

5 Fig 4 A-D, α1-Adrenergic receptors α1B-AR and α1D-AR partially mediate stretch-induced extracellular signal-regulated kinase (ERK) phosphorylation in vascular smooth muscle cells (VSMCs). A, Mechanical stretch (10% elongation for 1 hour, continually cultured for 6 hours) upregulates the expression of α1B-AR and α1D-AR mRNAs but not α1A-AR. B and C, α1B-AR and α1D-AR siRNAs (50 nM) significantly suppress the expression of VSMC α1B-AR and α1D-AR mRNAs. D, A graph of statistical results from three independent experiments that stretch stress (SS)-induced (10% elongation for 10 minutes) ERK phosphorylation in VSMCs can be partially inhibited by α1B-AR and α1D-AR siRNAs (50 nM). NC, Negative control; LIP, Lipofectamine 2000 control; SiC, nontargeting siRNA control; Siα1B, α1B-AR siRNA; Siα1D, α1D-AR siRNA; *P < .05 vs NC; #P < .05 vs SS. Journal of Vascular Surgery  , e3DOI: ( /j.jvs ) Copyright © 2013 Society for Vascular Surgery Terms and Conditions

6 Fig 5 A-I, α1-Adrenergic receptors (α1-ARs) partially mediate the additive effects of vascular smooth muscle cell (VSMC) proliferation (Ki67 expression) induced by combined treatment of cyclic stretch stress (SS) and norepinephrine (NE). Serum-starved VSMCs were pretreated with or without prazosin (Praz) for 1 hour and then subjected to cyclic SS or NE or NE plus cyclic SS for 1 hour and continually cultured 23 hours. The red-colored end products indicate the Ki67 antigens, and blue-colored end products indicate the nuclei of VSMCs. (Bar = 20 μm.) I, shows a graph of statistical results of A through H from three independent experiments. *P < .05 vs NC; aP < .05 vs NE; bP < .05 vs SS; cP < .05 vs SS+NE; $P < .05 vs SS+NE. Journal of Vascular Surgery  , e3DOI: ( /j.jvs ) Copyright © 2013 Society for Vascular Surgery Terms and Conditions

7 Fig 6 A-K, α1-Adrenergic receptors (α1-ARs) partially mediate the vein graft remodeling in vivo. Under anesthesia, the vena cava segments of mice were grafted into the carotid arteries of the recipient mice. The recipient mice postoperatively accepted prazosin (1.0 mg/kg/d) (E and I) or equal value of saline (C and G) via intraperitoneal injections for 2 weeks (C and E) or 4 weeks (G and I) and were sacrificed, and the vein grafts were fixed, embedded, sectioned, and stained with hematoxylin and eosin. The recipient mouse vena cava itself served as negative control (NC) (A and B). Arrow and stars indicate the wall thickness between vessel lumen and adventitia (arrows) and vessel lumens (stars) of the control vein (A and B) and vein grafts (C-J). B, D, F, H, and J, High-magnification areas of regions enclosed by a box (A, C, E, G, and I) (Bar = 50 μm). K, Statistical graphs of wall thickness of vein grafts from different groups (0, 2, and 4 weeks postoperatively). VG, Vein graft; VGP, vein graft plus prazosin. aP < .05 vs NC; bP < .05 vs VG2W; cP < .05 vs VG4W. Journal of Vascular Surgery  , e3DOI: ( /j.jvs ) Copyright © 2013 Society for Vascular Surgery Terms and Conditions

8 Fig 7 Potential signal pathway by which α1-adrenergic receptors (α1-ARs) partially mediate the additive effects of combined treatment of cyclic stretch stress (SS) and norepinephrine (NE) on vascular smooth muscle cell (VSMC) extracellular signal-regulated kinase (ERK) activation and proliferation. Hyperactivation of the sympathetic system results in increased catecholamine (eg, NE) in circulation. NE specifically binds to α1-ARs and initiates intracellular signaling including increased VSMC Gαq translocation, ERK phosphorylation, gene expression, and cell contraction and proliferation leading to the eventual development of hypertension. When hypertension occurs, hypertension-induced mechanical SS results in deformation of VSMCs and activates α1-ARs and downstream signaling, which further amplifies previous NE-induced signaling leading to additive effects of accelerated vascular remodeling. The effect can be partially inhibited by prasozin. The α1-ARs play a linker role between hypertension-induced SS and sympathetic system overdrive-increased NE in plasma. Journal of Vascular Surgery  , e3DOI: ( /j.jvs ) Copyright © 2013 Society for Vascular Surgery Terms and Conditions

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