Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster.
VSMCs respond to changes in the local environment by adjusting their phenotype from contractile to synthetic, a phenomenon known as phenotypic modulation or switching. Failure of VSMCs to acquire and maintain the contractile phenotype plays a key role in a number of major human diseases, including arteriosclerosis. Although several regulatory circuits that control differentiation of SMCs have been identified, the decisive mechanisms that govern phenotypic modulation remain unknown. Here, we demonstrate that the mouse miR-143/145 cluster, expression of which is confined to SMCs during development, is required for VSMC acquisition of the contractile phenotype. VSMCs from miR-143/145-deficient mice were locked in the synthetic state, which incapacitated their contractile abilities and favored neointimal lesion development. Unbiased high-throughput, quantitative, mass spectrometry-based proteomics using reference mice labeled with stable isotopes allowed identification of miR-143/145 targets; these included angiotensin-converting enzyme (ACE), which might affect both the synthetic phenotype and contractile functions of VSMCs. Pharmacological inhibition of either ACE or the AT1 receptor partially reversed vascular dysfunction and normalized gene expression in miR-143/145-deficient mice. We conclude that manipulation of miR-143/145 expression may offer a new approach for influencing vascular repair and attenuating arteriosclerotic pathogenesis.
Boettger
Thomas
T
Max-Planck-Institut für Herz- und Lungenforschung, Bad Nauheim, Germany. thomas.boettger@mpi-bn.mpg.de
Beetz
Nadine
N
Kostin
Sawa
S
Schneider
Johanna
J
Krüger
Marcus
M
Hein
Lutz
L
Braun
Thomas
T
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000166:cytology / Q000502:physiology; D001483:Base Sequence; D002216:Captopril / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D009119:Muscle Contraction / Q000235:genetics* / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D017539:Tunica Intima / Q000166:cytology
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; C543499:MIRN145a microRNA, mouse; D035683:MicroRNAs; C532884:MIRN143 microRNA, mouse; D002216:Captopril; D019808:Losartan
Circulation. 2001 Nov 20;104(21):2602-7
11714657
Cell. 2008 Jul 25;134(2):353-64
18662549
Eur J Cell Biol. 2003 Sep;82(9):473-82
14582535
Mol Cell. 2007 Jul 6;27(1):91-105
17612493
Circulation. 2002 Nov 5;106(19):2491-6
12417548
Cell. 2001 Jun 29;105(7):851-62
11439182
Exp Physiol. 2005 Jul;90(4):449-55
15890798
Genesis. 2003 Jun;36(2):81-2
12820168
Circ Res. 1996 Feb;78(2):188-95
8575061
Nat Neurosci. 2008 Jun;11(6):641-8
18454145
Cell. 2004 Jan 23;116(2):281-97
14744438
Genes Dev. 2004 Oct 1;18(19):2348-53
15466486
PLoS Biol. 2004 Nov;2(11):e363
15502875
Blood Vessels. 1991;28(1-3):262-7
1848125
Virchows Arch. 2000 Mar;436(3):257-70
10782885
Cell. 2007 Apr 20;129(2):303-17
17397913
Science. 1973 Jun 29;180(4093):1332-9
4350926
Circ Res. 2007 Jun 8;100(11):1579-88
17478730
Physiol Rev. 2004 Jul;84(3):767-801
15269336
J Physiol (Paris). 1979;75(5):463-505
533865
Nucleic Acids Res. 2008 Jan;36(Database issue):D149-53
18158296
J Mol Cell Cardiol. 2008 Mar;44(3):539-50
18207159
Arterioscler Thromb Vasc Biol. 2008 May;28(5):812-9
18276911
Cell. 2009 May 15;137(4):647-58
19409607
Am J Med. 2002 Feb 1;112(2):126-34
11835951
Genome Biol. 2003;4(4):R27
12702208
Nucleic Acids Res. 2008 Jan;36(Database issue):D154-8
17991681
Am J Pathol. 2004 Jul;165(1):1-10
15215157
Annu Rev Physiol. 1995;57:791-804
7778883
Neth Heart J. 2007;15(3):100-8
17612668
Mol Cell. 2007 Aug 3;27(3):435-48
17679093
Cell. 2003 May 2;113(3):329-42
12732141
Hypertension. 1997 Jan;29(1 Pt 2):150-7
9039095
J Biol Chem. 1987 Oct 25;262(30):14555-62
2822694
J Cell Biol. 1988 Dec;107(6 Pt 2):2575-86
3204121
Curr Biol. 2009 May 26;19(10):870-3
19375315
Nucleic Acids Res. 2005 Feb 24;33(4):e36
15731329
Cell. 2007 Jun 29;129(7):1401-14
17604727
Cell. 2007 Aug 10;130(3):395-8
17693247
Hypertension. 2001 Apr;37(4):1047-52
11304501
FEBS J. 2007 Sep;274(17):4375-84
17725712
J Am Coll Cardiol. 1990 Jun;15(7):1667-87
2188991
Exp Cell Res. 1997 Jan 10;230(1):45-9
9013705
Exp Physiol. 2007 Nov;92(6):1014-22
17644703
Circulation. 2000 Mar 28;101(12):1372-8
10736279
Mol Cell Proteomics. 2008 Apr;7(4):672-83
18045802
Proteomics. 2004 Jul;4(7):1985-8
15221759
Science. 2005 Dec 16;310(5755):1817-21
16308420
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2440-5
16461919
Mol Pharmacol. 1995 Oct;48(4):601-9
7476884
Circulation. 1994 May;89(5):2462-78
8181179
J Clin Invest. 2000 Jun;105(11):1605-12
10841519
J Biol Chem. 2008 Jul 4;283(27):18792-800
18468998